Repotrectinib overcomes crizotinib-resistant ROS1 G2032R
[Paragraph-level] PMCID: PMC10283448 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that repotrectinib is effective against crizotinib-resistant ROS1 G2032R, suggesting a correlation between the variant and response to therapy.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
DNMT3A exon 23 screening was performed on available samples coming from 288 AML patients aged from 18 to 65-year old and treated in Toulouse between 2000 and 2009. DNMT3A exon 23 mutations were detected in 39 patients (1
[Paragraph-level] PMCID: PMC3260002 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the detection of DNMT3A exon 23 mutations in AML patients, indicating that these mutations are associated with the disease, which supports their use in defining or confirming the disease. Oncogenic: The mention of DNMT3A mutations in AML patients suggests that these somatic variants contribute to tumor development or progression, as they are identified in a cancer context.
Gene→Variant (gene-first): 1788:R882 1788:R882C 1788:R882H 1788:R882P 1788:W893 1788:W893S
Genes: 1788
Variants: R882 R882C R882H R882P W893 W893S
A total of 3 out of 42 GC patients were METex14del positive (Table 3). All GC cases were MET IHC 3+ and the only case in the series with MET amplification. For example, one case was a 27-year old male patient who present
[Paragraph-level] PMCID: PMC4695055 Section: RESULTS PassageIndex: 5
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:T790M 673:V600E
Genes: 1956 673
Variants: T790M V600E
All 13 METex14del cases were further confirmed by qualitative RT-PCR using probes overlapping an exon 13-15 junction, a fusion transcript caused by exon 14 skipping. In all cases, although the absolute Ct (cycles to thre
[Paragraph-level] PMCID: PMC4695055 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage indicates that the variant c.3082+811A TTTTAACA > GGTTTGAT is found in all GI cancer samples, suggesting its association with the disease. Oncogenic: The presence of the variant in GI cancer samples implies a potential role in tumor development or progression, as it is discussed in the context of mutations in cancer.
Gene→Variant (gene-first): 7157:c.3082+811A TTTTAACA > GGTTTGAT
Genes: 7157
Variants: c.3082+811A TTTTAACA > GGTTTGAT
The patient cohort from the NEXT-1 trial (NCT02141152), which is an actively enrolling clinical trial for genomic profiling in cancer patients, was used (Figure 1). Of 428 patients enrolled and screened, sufficient RNAs
[Paragraph-level] PMCID: PMC4695055 Section: RESULTS PassageIndex: 2
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 4916:p.982_1028del47
Genes: 4916
Variants: p.982_1028del47
Based on our search criteria, a total of 41 studies, which enrolled 13,103 KRAS assessable patients with 18 percent (2,374) KRAS mutant positive cases, were eligible for inclusion in the present analyses. The process of
[Paragraph-level] PMCID: PMC4884999 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the frequency of KRAS mutations, specifically mentioning that the majority occur in codon 12 with G12C being the most common, indicating its association with lung cancer subtypes. Oncogenic: The mention of KRAS mutations, including G12C, in the context of lung adenocarcinoma suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 3845:G12C
Genes: 3845
Variants: G12C
We report two inflammatory myofibroblastic tumor (IMT) patients with ALK fusions (RRBP-ALK and TNS1-ALK, respectively). They both received tumor resection surgery and treatment with ALK inhibitors crizotinib followed by
[Paragraph-level] PMCID: PMC7568619 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The variant L1196Q is associated with the development of resistance to ALK inhibitors, and its identification guided the prescription of a newer ALK inhibitor, ceritinib, which resulted in a partial response in the patient. Oncogenic: The passage indicates that the L1196Q mutation is a secondary mutation that developed in the context of drug resistance, suggesting it contributes to tumor progression and the development of resistance to therapy.
Gene→Variant (gene-first): 238:L1196Q
Genes: 238
Variants: L1196Q
Pediatric glioblastomas (GBM) including diffuse intrinsic pontine gliomas (DIPG) are devastating brain tumors with no effective therapy. Here, we investigated clinical and biological impacts of histone H3.3 mutations. Fo
[Paragraph-level] PMCID: PMC3422615 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Diagnostic, Prognostic, Oncogenic
Justification: Diagnostic: K27M-H3.3 mutation defines clinically and biologically distinct subgroups in DIPG, indicating its use in classifying the disease. Prognostic: K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival, indicating its correlation with disease outcome. Oncogenic: The K27M-H3.3 mutation contributes to tumor development or progression in pediatric glioblastomas, as indicated by its prevalence in DIPG and association with specific copy number changes.
Gene→Variant (gene-first): 3021:G34V 3021:G34V/R 3021:K27M
Genes: 3021
Variants: G34V G34V/R K27M
Isocitrate dehydrogenases (IDHs) catalyse oxidative decarboxylation of isocitrate to alpha-ketoglutarate (alpha-KG). IDH1 functions in the cytosol and peroxisomes, whereas IDH2 and IDH3 are both localized in the mitochon
[Paragraph-level] PMCID: PMC3100313 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses heterozygous somatic mutations in IDH1, specifically the R132H variant, and its association with tumorigenesis in gliomas, indicating that this variant contributes to tumor development or progression. Functional: The passage mentions that mutations in IDH1, including R132H, cause loss of normal enzyme function and gain-of-function, leading to the accumulation of D-2-hydroxyglutarate, which alters the biochemical function of the enzyme.
Gene→Variant (gene-first): 3417:R132H
Genes: 3417
Variants: R132H
We studied 47 glioblastomas (WHO grade IV). Heterozygous mutations of IDH1 were found in 6/47 tumours (12%). All 6 mutations were single base substitutions c.395G>A occurring at residue R132, resulting in an arginine to
[Paragraph-level] PMCID: PMC3100313 Section: RESULTS PassageIndex: 2
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the frequency of heterozygous mutations of IDH1, specifically the c.395G>A variant, in glioblastomas, indicating its association with this disease subtype. Oncogenic: The presence of the IDH1 mutation (p.R132H) in glioblastomas suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 728294:R132 79944:arginine to histidine 728294:c.395G>A 3417:p.R132H
Genes: 728294 79944 3417
Variants: R132 arginine to histidine c.395G>A p.R132H
Diffuse Intrinsic Pontine Gliomas (DIPGs) are deadly paediatric brain tumours where needle biopsies help guide diagnosis and targeted therapies. To address spatial heterogeneity, here we analyse 134 specimens from variou
[Paragraph-level] PMCID: PMC4823825 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Oncogenic, Diagnostic
Justification: Oncogenic: The passage discusses how the K27M mutation contributes to tumorigenesis in DIPGs, indicating its role in tumor development and progression. Diagnostic: The K27M mutation is associated with the diagnosis of DIPGs, as it helps guide diagnosis and targeted therapies in these tumors.
Gene→Variant (gene-first): 8358:K27M
Genes: 8358
Variants: K27M
Recently, a rare activating mutation of AKT1 (E17K) has been reported in breast, ovarian, and colorectal cancers. However, analogous activating mutations in AKT2 or AKT3 have not been identified in any cancer lineage. To
[Paragraph-level] PMCID: PMC2570525 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Diagnostic, Oncogenic, Functional
Justification: Diagnostic: The passage discusses the identification of the AKT1 (E17K) mutation in various cancer types, indicating its association with melanoma and suggesting its role in defining the presence of this mutation in cancer specimens. Oncogenic: The passage states that the AKT1 E17K mutation is an activating mutation that contributes to tumor development, as evidenced by its identification in melanoma specimens and cell lines, indicating its role in cancer progression. Functional: The passage mentions that the AKT3 E17K mutation results in the activation of AKT when expressed in human melanoma cells, demonstrating a change in molecular function related to the variant.
Gene→Variant (gene-first): 207:AKT1 (E17K 207:E17K
Genes: 207
Variants: AKT1 (E17K E17K
Diffuse midline gliomas (DMGs) including diffuse intrinsic pontine gliomas (DIPGs) bearing lysine-to-methionine mutations in histone H3 at lysine 27 (H3K27M) are lethal childhood brain cancers. These tumors harbor a glob
[Paragraph-level] PMCID: PMC10161095 Section: ABSTRACT PassageIndex: 3
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how the lysine-to-methionine mutation at lysine 27 (H3K27M) contributes to tumor development and progression in diffuse midline gliomas, indicating its role as a somatic variant in cancer. Functional: The variant alters molecular function by affecting the levels of proteins in the SWI/SNF complex and influencing chromatin modifications, demonstrating its impact on biochemical processes within the tumor cells.
Gene→Variant (gene-first): 3021:lysine 27 55193:lysine-to-methionine
Genes: 3021 55193
Variants: lysine 27 lysine-to-methionine
Inherited mutations of transcription factors have recently been associated with susceptibility to acute leukemia. Here we report two unrelated kindreds with inherited mutations in ETV6, the gene encoding the transcriptio
[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 3
Evidence Type(s): Predisposing, Functional
Justification: Predisposing: The passage discusses inherited mutations in ETV6 that confer susceptibility to acute leukemia, indicating a germline origin and inherited risk for developing the disease. Functional: The passage describes how the ETV6 mutations (L349P and N385fs) alter the protein's localization and its ability to regulate gene expression, demonstrating a change in molecular function.
Gene→Variant (gene-first): 2120:L349P 2120:N385fs
Genes: 2120
Variants: L349P N385fs
Somatic mutations affecting ETV6 often occur in acute lymphoblastic leukemia (ALL), the most common childhood malignancy. The genetic factors that predispose to ALL remain poorly understood. Here we identify a novel germ
[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predisposing, Oncogenic, Functional
Justification: Predisposing: The passage describes a germline ETV6 p. L349P mutation identified in a kindred affected by thrombocytopenia and ALL, indicating an inherited risk for developing the disease. Oncogenic: The ETV6 p. N385fs mutation was found in leukemic cells and is associated with the deletion of wild type ETV6, suggesting its contribution to tumor development in the context of leukemia. Functional: The enforced expression of the ETV6 mutants showed impaired nuclear localization and a significantly reduced ability to regulate the transcription of ETV6 target genes, indicating an alteration in molecular function.
Gene→Variant (gene-first): 2120:p. L349P 2120:p. N385fs
Genes: 2120
Variants: p. L349P p. N385fs
P05 was a female patient with EGFR exon 19 deletion-mutant stage IV LUAD with bone metastasis, and ERBB2DeltaEx16 was identified from her plasma sample after progression on osimertinib plus crizotinib ( Table 2 ; Figure
[Paragraph-level] PMCID: PMC9859631 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses various mutations, including Y1230H, D1288N L1195I, and L1195V, which are described as secondary mutations associated with MET TKI resistance, indicating a correlation with treatment response. Oncogenic: The mention of mutations contributing to resistance against targeted therapies suggests that these variants may play a role in tumor development or progression, particularly in the context of lung cancer.
Gene→Variant (gene-first): 79811:D1288N L1195I 79811:L1195V 79811:Y1230H 2064:c.1899-936_1946+520del
Genes: 79811 2064
Variants: D1288N L1195I L1195V Y1230H c.1899-936_1946+520del
P03 was a female patient with EGFR L858R-mutant advanced LUAD with bone metastasis. ERBB2DeltaEx16 was detected after disease progression with osimertinib using her plasma samples but not in the paired tissue rebiopsy (
[Paragraph-level] PMCID: PMC9859631 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the presence of the EGFR L858R variant in a patient with advanced LUAD and its association with resistance to osimertinib, indicating a correlation with treatment response. Oncogenic: The mention of the EGFR L858R variant and its role in the context of advanced LUAD suggests that it contributes to tumor development or progression, particularly as it is associated with resistance mechanisms.
Gene→Variant (gene-first): 2064:D769Y 2064:L755S 1956:L858R 2064:c.1899-32_1909del
Genes: 2064 1956
Variants: D769Y L755S L858R c.1899-32_1909del
Of the 21 unique ERBB2DeltaEx16 variants detected from Chinese patients, 9 involved complete deletion of exon 16, 3 were deletions or point mutations involving splice donors, and 9 deletions or point mutations affecting
[Paragraph-level] PMCID: PMC9859631 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Predictive
Justification: Diagnostic: The passage discusses the detection of ERBB2 variants in patients, indicating their association with specific cases, which supports their use in defining or classifying a disease subtype. Predictive: The mention of the novel variant ERBB2 c.1899-2A>G being detected after treatment suggests a potential correlation with treatment response, indicating its relevance in predicting therapy outcomes.
Gene→Variant (gene-first): 2064:c.1899-2A>G 2064:c.1899-880_1946+761del
Genes: 2064
Variants: c.1899-2A>G c.1899-880_1946+761del
In clinical practice, there are a number of cancer patients with clear family histories, but the patients lack mutations in known familial cancer syndrome genes. Recent advances in genomic technologies have enhanced the
[Paragraph-level] PMCID: PMC5111006 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage indicates that the homozygous CHEK2 variant p.R474C was contributory to familial cancer, and the inactivation of CHEK2 in mice led to cancers in multiple organs, suggesting a role in tumor development. Functional: The variant p.R474C alters the tertiary structure of the CHK2 protein by disrupting a salt bridge, and subsequent analysis showed that it was unstable and scarcely activated, indicating a change in molecular function.
Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C
Genes: 11200
Variants: p.R474 p.R474C
Among the variants detected in the runs of homozygosity common to both siblings, five were recorded as disease-associated variants in the HGMD public entries. However, they are related to diabetes or insulin secretion (r
[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 18
Evidence Type(s): Diagnostic, Predisposing
Justification: Diagnostic: The passage states that the variants are recorded as disease-associated variants, indicating their use in defining or classifying diseases such as diabetes, carotid intima media thickness, and oligospermia. Predisposing: The variants mentioned are associated with inherited conditions, suggesting they confer an inherited risk for developing diseases, although the germline nature is implied rather than explicitly stated.
Gene→Variant (gene-first): 440822:rs11703684 6289:rs2468844 3767:rs5215 3767:rs5219 6833:rs757110
Genes: 440822 6289 3767 6833
Variants: rs11703684 rs2468844 rs5215 rs5219 rs757110
We surveyed variants in potential hereditary loci including those in TP53 (causative gene for Li-Fraumeni syndrome), BRCA2 (causative gene for hereditary breast/ovarian cancer), and mismatch repair genes (MSH2, MSH6, PMS
[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 17
Evidence Type(s): Predisposing, Diagnostic
Justification: Predisposing: The passage discusses variants in hereditary loci, specifically mentioning TP53 and BRCA2, which are associated with inherited cancer syndromes, indicating a potential inherited risk for developing disease. Diagnostic: The passage mentions the classification of variants as "Benign" or of "Uncertain significance," which relates to their use in defining or classifying disease risk or status.
Gene→Variant (gene-first): 7157:p.P72R 675:p.V2466A 7157:rs1042522 2956:rs1042821 4072:rs1126497 675:rs169547 5395:rs1805323 5395:rs2228006 4436:rs2303424
Genes: 7157 675 2956 4072 5395 4436
Variants: p.P72R p.V2466A rs1042522 rs1042821 rs1126497 rs169547 rs1805323 rs2228006 rs2303424
CHK2 is a cell cycle checkpoint regulator activated by DNA damage. The above analysis and the function of CHK2 suggest that CHEK2 is a contributory gene for this familial case. We therefore examined the function of CHK2
[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 15
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the p.R474C variant alters the molecular function of the CHK2 protein, demonstrating that it is poorly expressed and activated by DNA damage compared to the wild-type protein. Oncogenic: The context implies that the p.R474C variant contributes to tumor development or progression by affecting the function of a cell cycle checkpoint regulator, which is critical in the context of cancer biology.
Gene→Variant (gene-first): 11200:p.R474C
Genes: 11200
Variants: p.R474C
CHK2 p.R474C Protein Is Poorly Activated in the Cell upon DNA Damage
[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional
Justification: Functional: The passage indicates that the p.R474C variant affects the activation of the CHK2 protein in response to DNA damage, suggesting an alteration in its molecular function.
Gene→Variant (gene-first): 11200:p.R474C
Genes: 11200
Variants: p.R474C
The tertiary structure of FCGRT-immunoglobulin Fc fragment complex was determined. p.R210 contacts the carboxyl terminus of the immunoglobulin Fc fragment. Although there is a salt bridge between p.R210 and the Fc fragme
[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variant p.R210 and its substitution p.R210Q relate to the structure and potential function of the protein, indicating that p.R210Q is not likely to affect the function and structure of the protein.
Gene→Variant (gene-first): 2217:p.R210 2217:p.R210Q
Genes: 2217
Variants: p.R210 p.R210Q
Second, we examined how the amino acid substitutions affect the tertiary structure of the proteins. The tertiary structure of the inactive CHK2 homodimer (PDB code: 3i6w) is shown in Figure 4B. p.R474 is located away fro
[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 11
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the variant p.R474C alters the salt bridge formation and is likely to make the protein unstable, indicating an alteration in molecular function. Oncogenic: The variant p.R474C is described as "disease causing" and likely interferes with protein function, suggesting a role in tumor development or progression.
Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C
Genes: 11200
Variants: p.R474 p.R474C
First, the effects of these missense variants were predicted using the Variant Effect Predictor at Ensembl, for which SIFT (Sorting Intolerant from Tolerant) and PolyPhen (Polymorphism Phenotyping) are used. Three varian
[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variant p.R474 in CHEK2 was analyzed for its effect on protein function based on evolutionary conservation, indicating that it alters molecular or biochemical function.
Gene→Variant (gene-first): 11200:p.R474
Genes: 11200
Variants: p.R474
The female patient, FL2, was 6 years older than the male patient. At the age of 38, she was diagnosed with uterine myoma and developed multiple primary lung cancer at the age of 60 with no history of smoking. Three prima
[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 4
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the presence of the L858R mutation in the context of lung cancer, indicating its potential role in tumor development or progression.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
Ninety-two of the 93 tumors were amenable to data analysis. TP53 was the most common mutation, occurring in 47 (51%) patients, followed by CDKN2A (n=23, 25%), CCND1 (n=22, 24%), and PIK3CA (n=19, 21%). The total mutation
[Paragraph-level] PMCID: PMC6333965 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage mentions that PIK3CA E545K and CDKN2A R58X are potentially targetable alterations, indicating their association with specific tumor characteristics or responses, which aligns with diagnostic evidence. Oncogenic: The variants PIK3CA E545K and CDKN2A R58X are described as potentially targetable alterations, suggesting their role in tumor development or progression, which supports oncogenic evidence.
Gene→Variant (gene-first): 5290:E545K 1029:R58X
Genes: 5290 1029
Variants: E545K R58X
Single nucleotide variants (SNVs) and insertions and deletions (InDels) were identified in mouse ccRCCs versus matched liver. The most frequent SNVs were C>A/G>T transversions, C>T/G>A transitions and A>G/T>C transitions
[Paragraph-level] PMCID: PMC5509015 Section: RESULTS PassageIndex: 14
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the frequency and types of mutations observed in human ccRCC, indicating that these mutations are associated with the disease, thus providing evidence for their role in defining or classifying the disease. Oncogenic: The passage describes mutations in primary cilium-related genes that contribute to the formation of ccRCC precursor lesions in mice, indicating that these somatic variants play a role in tumor development.
Gene→Variant (gene-first): 7428:A>G 7428:C>A 7428:C>T 7428:G>A 7428:G>T 7428:T>C
Genes: 7428
Variants: A>G C>A C>T G>A G>T T>C
To functionally test this idea in mice, we genetically deleted Vhl together with two tumour suppressor genes that encode proteins that function as the key controllers of cell cycle entry in the p53/G1-S network, namely T
[Paragraph-level] PMCID: PMC5509015 Section: RESULTS PassageIndex: 5
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the deletion of Trp53 in mice and its contribution to tumor development, as evidenced by the increased incidence and earlier onset of tumors in VhlDelta/DeltaTrp53Delta/DeltaRb1Delta/Delta mice compared to other genotypes. Functional: The deletion of Trp53 is described in the context of its role in the p53/G1-S network, indicating that it alters the molecular function related to cell cycle control and tumorigenesis.
Gene→Variant (gene-first): 7428:Trp53 deletion
Genes: 7428
Variants: Trp53 deletion
The observation that K-RasG12D and switch 2 insertion mutant proteins are defective for PI3K binding and Akt activation suggested that this might alter effector pathway dependencies. To address this question, we exposed
[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 15
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of cells expressing K-RasG12D to specific therapies, indicating a correlation between the variant and response to treatment with MEK and PI3K inhibitors. Oncogenic: The mention of K-RasG12D in the context of transformed Ba/F3 cells suggests that this somatic variant contributes to tumor development or progression, as it is involved in cytokine-independent growth.
Gene→Variant (gene-first): 3845:K-RasG12D
Genes: 3845
Variants: K-RasG12D
Together with prior structural modelling predictions, these biochemical data prompted us to directly assess the ability of WT and mutant K-Ras proteins to bind to effectors in vitro. As expected, His-K-Ras WT bound GST-R
[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the ability of mutant K-Ras proteins to bind to effectors in vitro, indicating that the variants alter molecular interactions, specifically the binding to FLAG-p110alpha. Oncogenic: The mention of K-RasG12D and the other mutant variants in the context of their binding interactions suggests that these somatic variants contribute to tumor development or progression through their altered functional properties.
Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D 5290:Y64G
Genes: 5295 3845 5290
Variants: A66dup K-RasG12D Y64G
To assess how acute activation of K-Ras duplication mutants modulates effector pathway activation, we engineered tetracycline inducible GFP-K-Ras constructs and introduced them into Ba/F3 cells (Supplementary Fig. 4). In
[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the K-RasG12D variant alters the levels of pERK and pAkt, indicating a change in molecular function related to signaling pathways. Oncogenic: The K-RasG12D variant is implicated in modulating effector pathway activation, which suggests its role in tumor development or progression.
Gene→Variant (gene-first): 3845:K-RasG12D
Genes: 3845
Variants: K-RasG12D
Expression of K-RasG12D and each tandem duplication mutant, but not WT K-Ras, transformed interleukin 3 (IL-3)-dependent Ba/F3 cells to cytokine-independent growth (Supplementary Fig. 3a). Ba/F3 cells expressing K-RasG12
[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 11
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage describes how the K-RasG12D variant and tandem duplication mutants transform Ba/F3 cells to cytokine-independent growth, indicating their role in tumor development or progression. Functional: The passage mentions that Ba/F3 cells expressing K-RasG12D and the tandem duplication mutants had elevated levels of Ras-GTP, suggesting that these variants alter molecular function related to Ras signaling.
Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D
Genes: 5295 3845
Variants: A66dup K-RasG12D
To directly test these predictions, we produced N-terminal histidine fusions encoding amino acids 1-166 of K-RasG60_A66dup or K-RasE62_A66dup, and compared their biochemical properties with WT K-Ras and K-RasG12D (Supple
[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the variants K-RasG60_A66dup and K-RasE62_A66dup alter the biochemical properties of K-Ras, specifically their GTPase activity and response to GAP stimulation, indicating a change in molecular function. Oncogenic: The variants are described in the context of their role in accumulating in the active GTP conformation and exhibiting impaired GTPase activity, which suggests their contribution to tumor development or progression.
Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D
Genes: 5295 3845
Variants: A66dup K-RasG12D
We next examined published crystal structures to model potential effects of switch 2 insertions on the following: (1) the positions of critical residues involved in intrinsic catalysis such as Glutamine 61 (Q61); (2) the
[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 7
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the variant Glutamine 61 (Q61) may alter protein-protein interactions and the structural dynamics of Ras, indicating a change in molecular function due to the predicted effects of switch 2 insertions. Oncogenic: The analysis suggests that the alterations in the Ras protein structure, particularly involving Q61, may contribute to the GTP conformation of Ras, which is associated with tumor development and progression.
Gene→Variant (gene-first): 3845:Glutamine 61 3845:Q61
Genes: 3845
Variants: Glutamine 61 Q61
A hypersensitive pattern of colony-forming unit granulocyte macrophage (CFU-GM) progenitor formation in response to colony-stimulating factor (GM-CSF) is a cellular hallmark of JMML. To ask whether K-Ras insertion mutant
[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 5
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses how the K-RasG12D variant induces cytokine-independent colony formation and contributes to abnormal growth patterns in hematopoietic progenitor cells, indicating its role in tumor development. Functional: The variant K-RasG12D alters the growth response of progenitor cells to GM-CSF, demonstrating a change in molecular function related to colony formation.
Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D
Genes: 5295 3845
Variants: A66dup K-RasG12D
Juvenile myelomonocytic leukaemia (JMML) is an aggressive myeloproliferative neoplasm (MPN) characterized by driver Ras pathway mutations in 85% of cases, including known oncogenic KRAS and NRAS substitutions. We discove
[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage describes a partial duplication of the K-Ras gene that is associated with juvenile myelomonocytic leukaemia (JMML), indicating that the variant contributes to tumor development or progression. Functional: The immunoblot analysis shows that the variant alters the molecular function of K-Ras, as evidenced by the detection of a band with reduced electrophoretic mobility compared to normal Ras protein, indicating a change in protein behavior.
Gene→Variant (gene-first): 3845:c.178_198dup 3845:c.184_198dup
Genes: 3845
Variants: c.178_198dup c.184_198dup
Finally, we tested the effects of the combination therapies on cell proliferation in osimertinib-resistant cell lines. Similar to RPC-9/NaqR cells, the osimertinib-resistant cell lines were derived from RPC-9 cells, desi
[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the effects of combination therapies on cell proliferation in osimertinib-resistant cell lines, indicating a relationship between the presence of the T790M mutation and the response to therapy, specifically mentioning osimertinib and naquotinib. Oncogenic: The T790M mutation is maintained in the osimertinib-resistant RPC-9/OsiR cells, suggesting its role in tumor development or progression, particularly in the context of resistance to therapy.
Gene→Variant (gene-first): 1956:C797S 1956:T790M
Genes: 1956
Variants: C797S T790M
Next we investigated RPC-9/NaqR cells, which were derived from gefitinib-resistant lung adenocarcinoma cell lines (RPC-9 cells harboring the EGFR exon 19del and T790M mutations). Exposure to naquotinib inhibited the phos
[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses gefitinib-resistant lung adenocarcinoma cell lines harboring the EGFR exon 19del and T790M mutations, indicating a correlation with resistance to therapy, specifically gefitinib. Oncogenic: The mention of the EGFR exon 19del and T790M mutations in the context of gefitinib resistance suggests that these somatic variants contribute to tumor development or progression in lung adenocarcinoma.
Gene→Variant (gene-first): 1956:19del 1956:T790M
Genes: 1956
Variants: 19del T790M
To further examine the role of MET in EGFR-TKI-naive cancer cells, we developed another resistant cell line from EGFR-TKI-naive lung cancer cells, HCC827, which harbor the EGFR exon 19del. The resistant cell line, design
[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 8
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The passage discusses the role of the EGFR exon 19del variant in the development of a resistant cell line, indicating that this somatic variant contributes to tumor progression and resistance mechanisms in lung cancer cells. Predictive: The passage mentions that the combination of EGFR-TKIs and MET inhibitors showed an excellent inhibitory effect on cell proliferation in the resistant cell line, suggesting a correlation between the variant and response to therapy.
Gene→Variant (gene-first): 1956:19del
Genes: 1956
Variants: 19del
Next, we assessed the effects of several generations of EGFR-TKIs in these naquotinib-resistant cell lines. The resistant cell lines exhibited 52- to 157-fold resistance to naquotinib compared with each parental cell lin
[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the acquired EGFR C797S mutation in the context of resistance to osimertinib, indicating that this variant correlates with resistance to a specific therapy. Oncogenic: The C797S mutation is described as contributing to resistance in cell lines, suggesting its role in tumor progression or development in the context of EGFR-TKI treatment.
Gene→Variant (gene-first): 1956:C797S
Genes: 1956
Variants: C797S
First, to explore the mechanism of resistance to naquotinib, we established naquotinib-resistant lung cancer cells using a cell line-based model. The following cell lines were examined: 1. EGFR-TKI-naive PC-9 cells harbo
[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the establishment of naquotinib-resistant lung cancer cells and mentions the effectiveness of naquotinib in inhibiting cell proliferation, indicating a correlation between the variants (19del and T790M) and resistance to therapy. Oncogenic: The presence of the T790M mutation in acquired gefitinib-resistant cells suggests that it contributes to tumor development or progression, as it is associated with resistance mechanisms in lung cancer.
Gene→Variant (gene-first): 1956:19del 1956:T790M
Genes: 1956
Variants: 19del T790M
We also investigated whether drug efficacy is dependent on the FGFR variants in patients. For this purpose, we retrospectively collected variant information and drug efficacy data related to FGFR inhibitors in 399 cases
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 22
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between the FGFR3 S249C variant and the response to treatment with FGFR TKIs, indicating that patients with this mutation exhibited partial or complete responses, which aligns with predictive evidence. Oncogenic: The FGFR3 S249C variant is described as the most frequent mutation of FGFR3, suggesting its role in tumor development or progression, which supports its classification as oncogenic.
Gene→Variant (gene-first): 2261:S249C
Genes: 2261
Variants: S249C
Furthermore, the existence of concurrent mutations between FGFRs and the genes involved in different pathways, such as PIK3CA, PTEN, AKT1/2/3, and MAP2K1 was investigated. Indeed, concurrent mutations with PIK3CA were fr
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 21
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the mutations E545K, E542K, and H1047R are described as "oncogenic mutations," suggesting they contribute to tumor development or progression.
Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R
Genes: 5290
Variants: E542K E545K H1047R
More than 400 types of FGFR compound mutations were observed in the COSMIC database, and 34 types of those were reported in more than two samples (Fig. 7a). The most frequent compound mutation is the combination of S249C
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 20
Evidence Type(s): Oncogenic, Predictive
Justification: Oncogenic: The passage discusses the transforming activities of FGFR3 S249C compound mutations, indicating that these mutations contribute to tumor development or progression as demonstrated by their evaluation in 3T3 and Ba/F3 cells. Predictive: The passage mentions the sensitivity to E7090 and erdafitinib in relation to the mutations, indicating a correlation with treatment response, which aligns with predictive evidence.
Gene→Variant (gene-first): 2261:K650E 2261:K650M 2261:S249C 2261:Y373C
Genes: 2261
Variants: K650E K650M S249C Y373C
Next, we measured the effectiveness of E7090 and erdafitinib in vivo. Mouse 3T3 fibroblasts expressing FGFR1 N546K, FGFR2 N549K, FGFR3 R248C, FGFR3 K650M, or FGFR3 K650N were injected into nude mice that were subsequentl
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the effectiveness of E7090 and erdafitinib in treating tumors with specific variants, indicating a correlation between the variants and the response to these therapies. Oncogenic: The variants are described in the context of tumor growth and response to treatment, suggesting that they contribute to tumor development or progression.
Gene→Variant (gene-first): 2261:K650M 2261:K650N 2260:N546K 2263:N549K 2261:R248C
Genes: 2261 2260 2263
Variants: K650M K650N N546K N549K R248C
Inhibition of FGFRs and downstream signaling pathways by FGFR TKIs was evaluated through immunoblot analyses (Fig. 3c). While phosphorylation of FGFR3 K650M was suppressed by E7090 at 100 nM, that of FGFR3 K650N was decr
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 14
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the response of FGFR3 variants K650M and K650N to FGFR TKIs, indicating their sensitivity to specific therapies, which aligns with predictive evidence. Functional: The passage describes the alteration of phosphorylation status of the FGFR3 variants K650M and K650N in response to treatment, indicating a change in molecular function due to the variants.
Gene→Variant (gene-first): 2261:K650M 2261:K650N
Genes: 2261
Variants: K650M K650N
Hierarchical clustering analysis was conducted to evaluate the similarity of FGFR inhibitors and FGFR variants using drug sensitivity data of Fig. 4 (Supplementary Fig. 11). FGFR variants were classified into four cluste
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity and resistance of FGFR variants, including N546K and N549D/K, to FGFR inhibitors, indicating a correlation with response to therapy. Oncogenic: The passage mentions that KRAS G12V is part of a cluster composed mainly of oncogenic variants, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 3845:G12V 2260:N546K 2263:N549D/K
Genes: 3845 2260 2263
Variants: G12V N546K N549D/K
To validate the results of the pooled assay, the respective variants to which drug sensitivity was different among TKIs were further analyzed. Interestingly, in the evaluation with the MANO method, different missense var
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses how different missense variants at specific amino acid positions in FGFR2 and FGFR3 correlate with varying drug sensitivities to FGFR inhibitors, indicating a relationship between the variants and treatment response.
Gene→Variant (gene-first): 2263:K656 2263:K656E/M 2263:N549 2263:N549D/H
Genes: 2263
Variants: K656 K656E/M N549 N549D/H
The drug sensitivity of transformed FGFR variants was also assessed through the MANO method. The mixture of 3T3 cells expressing different types of FGFR variants were treated with eight different targeted drugs, and drug
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the drug sensitivity of FGFR variants in response to various targeted therapies, indicating that certain variants are sensitive or resistant to specific inhibitors, which aligns with predictive evidence. Oncogenic: The context of transformed FGFR variants suggests that these somatic mutations contribute to tumor development or progression, particularly as they are assessed for their response to targeted therapies.
Gene→Variant (gene-first): 2264:N535K 2260:N546K 2263:N549D/K 2263:V550L
Genes: 2264 2260 2263
Variants: N535K N546K N549D/K V550L
The mRNA expression levels were similar among variants in previous studies using the MANO method. We evaluated the mRNA and protein expression of several FGFR3 variants using real-time PCR and western blotting. While a s
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the evaluation of mRNA and protein expression levels of the R248H variant, indicating that it alters protein expression compared to oncogenic variants, which relates to its molecular function. Oncogenic: The passage implies that the R248H variant is classified as a non-oncogenic variant, contrasting it with oncogenic variants, suggesting its role in tumor development or progression is not supported.
Gene→Variant (gene-first): 1956:R248H
Genes: 1956
Variants: R248H
Thus, we utilized the MANO method to compare the number of 3T3 cells expressing each FGFR variant between Day 3 and Day 18 in the assessment of the transforming potential (Fig. 2 and Supplementary Fig. 3). In parallel wi
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the transforming potential of various FGFR variants, indicating that certain mutations contribute to tumor development or progression, as evidenced by their significant transforming activities in assays.
Gene→Variant (gene-first): 2261:G370C 2261:G380E/R 2261:K650E/M 2263:K659E 2263:N549H 2261:R248C 2261:S249C 6867:S342F 2261:S371C 2263:W290C 2261:Y373C
Genes: 2261 2263 6867
Variants: G370C G380E/R K650E/M K659E N549H R248C S249C S342F S371C W290C Y373C
FGFRs are highly conserved transmembrane receptor tyrosine kinases, comprised of an extracellular domain with three Ig-like domains, followed by a transmembrane domain and a tyrosine kinase domain (Fig. 1a). Firstly, the
[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic
Justification: Oncogenic: The V550L mutation in FGFR4 is mentioned in the context of rhabdomyosarcoma, suggesting its contribution to tumor development.
Gene→Variant (gene-first): 2260:K656E 2260:N546K 2261:S249C 2263:S252W 2263:V550L
Genes: 2260 2261 2263
Variants: K656E N546K S249C S252W V550L
IDH1 R132H and ATRX KO have similar levels of PARP inhibitor sensitivity.
[Paragraph-level] PMCID: PMC8203843 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that IDH1 R132H is associated with sensitivity to PARP inhibitors, which correlates the variant with a specific therapy response.
Gene→Variant (gene-first): 3417:R132H
Genes: 3417
Variants: R132H
FLT3 mutations are the most frequently identified genetic alterations in acute myeloid leukemia (AML) and are associated with poor prognosis. Multiple FLT3 inhibitors are in various stages of clinical evaluation. However
[Paragraph-level] PMCID: PMC8255005 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the resistance of FLT3 mutations, specifically F691L, to FLT3 inhibitors and highlights the efficacy of KX2-391 in overcoming this resistance, indicating a correlation with treatment response. Oncogenic: The FLT3 mutations, including D835 and F691, are described as contributing to tumor development and progression in acute myeloid leukemia (AML), which supports their classification as oncogenic variants.
Gene→Variant (gene-first): 2322:D835 2322:D835Y 2322:F691 2322:F691L
Genes: 2322
Variants: D835 D835Y F691 F691L
To get a deeper insight into the molecular characteristics of this group, we analyzed next-generation sequencing results from 17 cases. Seven cases were analyzed using the Heidelberg 130 gene panel, six cases were sequen
[Paragraph-level] PMCID: PMC7785563 Section: RESULTS PassageIndex: 12
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage indicates that 90% of the cases harbored IDH1-R132H mutations, which are associated with conventional supratentorial IDH-mutant astrocytomas, suggesting a role in defining or classifying the disease. Oncogenic: The presence of IDH1-R132H mutations in the tumors suggests that this somatic variant contributes to tumor development or progression, as it is commonly found in a specific type of cancer.
Gene→Variant (gene-first): 3417:R132H
Genes: 3417
Variants: R132H
In metastatic breast cancer, HER2 activating mutations frequently co-occur with mutations in the PIK3CA, TP53, or E-cadherin genes. Of these co-occurring mutations, HER2 and PIK3CA mutations are the most prevalent gene p
[Paragraph-level] PMCID: PMC10527017 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the resistance of HP breast cancers to the pan-HER tyrosine kinase inhibitor, neratinib, and the effectiveness of combining neratinib with trastuzumab deruxtecan and CDK4/6 inhibitors, indicating a correlation with treatment response. Oncogenic: The study involves genetically engineered mice with the HER2V777L mutation, showing accelerated tumor formation and increased invasion, which supports the notion that this somatic variant contributes to tumor development and progression.
Gene→Variant (gene-first): 2064:V777L
Genes: 2064
Variants: V777L
ALK-break positive non-small cell lung cancer (NSCLC) patients initially respond to crizotinib, but resistance occurs inevitably. In this study we aimed to identify fusion genes in crizotinib resistant tumor samples. Re-
[Paragraph-level] PMCID: PMC4821611 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses ALK mutations (p.C1156Y and p.G1269A) in the context of crizotinib resistance, indicating a correlation between these variants and resistance to the therapy. Oncogenic: The ALK mutations are described as being detected in post-treatment tumor samples, suggesting their contribution to tumor development or progression in the context of crizotinib resistance.
Gene→Variant (gene-first): 238:p.C1156Y 238:p.G1269A
Genes: 238
Variants: p.C1156Y p.G1269A
Mutations in ALK, EGFR and KRAS have been reported to confer resistance against crizotinib. To determine presence of mutations in these genes in the three post-treatment samples, we inspected the RNA-seq bam files in IGV
[Paragraph-level] PMCID: PMC4821611 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses mutations in the ALK gene, specifically p.C1156Y and p.G1269A, which have been reported to confer resistance against crizotinib, indicating a correlation with treatment response. Oncogenic: The presence of mutations in the ALK gene, such as p.C1156Y and p.G1269A, suggests that these somatic variants contribute to tumor development or progression, as they were identified in post-treatment tumor samples.
Gene→Variant (gene-first): 238:c.3467G>A 238:c.3806G>C 238:p.C1156Y 238:p.G1269A
Genes: 238
Variants: c.3467G>A c.3806G>C p.C1156Y p.G1269A
In TERT-NHUC, abolishing PLCgamma1 phosphorylation significantly reduced the increase in saturation density associated with S249C FGFR3 (13% vs. 24%, p=0.05) (Figure 6a), suggesting that PLCgamma1 signaling contributes t
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 23
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the S249C and K652E mutations affect cell viability and signaling pathways, indicating that these variants alter molecular or biochemical functions related to cell growth and density. Oncogenic: The evidence suggests that the S249C and K652E mutations contribute to tumor development or progression by affecting cell cycle phases and viability, which are indicative of cancer-driving behavior.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y762F
Genes: 2261
Variants: K652E S249C Y762F
To clarify whether the lack of constitutive PLCgamma1 phosphorylation may explain the different phenotypic behavior associated with the K652E mutation, we used a construct encoding a S249C FGFR3 protein with a mutated PL
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 22
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the S249C+Y762F FGFR3 mutant protein's ability to induce morphological transformation and increased proliferation in NIH-3T3 cells, indicating its role in tumor development or progression. Functional: The passage describes how the S249C+Y762F mutation affects the phosphorylation of PLCgamma1 and alters the activation of downstream signaling pathways, demonstrating a change in molecular function.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y762F
Genes: 2261
Variants: K652E S249C Y762F
As expected, FGF1 induced phosphorylation of FRS2alpha, ERK1/2 and PLCgamma1 in normal urothelial cells over-expressing wildtype FGFR3 (Figure 4b). Consistent with their complete ligand-independence, FGF1 treatment faile
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 20
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the K652E, S249C, and Y375C mutations alter the signaling response to FGF1 treatment, indicating that these variants affect molecular function related to phosphorylation and activation of signaling pathways. Oncogenic: The context of the mutations being discussed in relation to their effects on signaling pathways suggests that they may contribute to tumor development or progression, particularly given the focus on their responses in cancer-related cellular contexts.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
We next examined whether cells expressing wildtype and mutant FGFR3 were responsive to FGF1 stimulation in terms of receptor activation (Figure 4a, Supplementary Figure 5) and signaling (Figure 4b, Supplementary Figure 5
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 19
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the response of cells expressing mutant FGFR3 variants (S249C, Y375C, K652E) to FGF1 stimulation, indicating a correlation with receptor activation and signaling, which relates to treatment response. Functional: The passage describes how the variants S249C, Y375C, and K652E affect the phosphorylation of FGFR3, indicating that these mutations alter the molecular function of the receptor in response to ligand stimulation.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
Signaling was examined in cells at various degrees of confluence, in full and depleted medium (Figure 3c, Supplementary Figure 4b). In all conditions tested, no differences were observed between mutant and control cells
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 16
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the increased phosphorylation of PLCgamma1 specifically in cells expressing the S249C and Y375C FGFR3 variants, indicating that these variants alter molecular function. Oncogenic: The mention of increased phosphorylation of signaling proteins in cells expressing the FGFR3 mutants suggests that these variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
To investigate the reason for the differential behavior of cells expressing K652E FGFR3, we assessed the phosphorylation levels of FGFR3 mutant proteins and downstream effectors in urothelial cells. All mutant forms of F
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 15
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the K652E, S249C, and Y375C variants of FGFR3 alter phosphorylation levels and dimerization behavior, indicating changes in molecular function. Oncogenic: The variants are described in the context of their constitutive activation and behavior in urothelial cells, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
Three proteins involved in cell survival, MCL1, BCL-XL, and BCL2, were up-regulated in confluent cells expressing all types of mutant FGFR3 (Figure 2d, Supplementary Figure 3b). Surprisingly, there was no difference in t
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the expression of proteins involved in cell survival and suggests that the K652E variant may alter the viability of cells, indicating a change in molecular function. Oncogenic: The context implies that the K652E variant contributes to tumor behavior by affecting cell viability, which is a characteristic of oncogenic variants.
Gene→Variant (gene-first): 2261:K652E
Genes: 2261
Variants: K652E
Consistent with their altered cell cycle profile, confluent TERT-NHUC expressing mutant FGFR3 exhibited changes in cell cycle-related proteins (Figure 2d, Supplementary Figure 3a). Whilst in control cells the expression
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variants S249C, Y375C, and K652E FGFR3 alter the expression and phosphorylation of cell cycle-related proteins, indicating a change in molecular function.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
Cells expressing S249C and Y375C FGFR3 were significantly more viable at confluence compared to controls or cells expressing wildtype FGFR3 (p<=0.001). On days 12 (Figure 2c) and 15 (data not shown), on average 45% of S2
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the viability of cells expressing specific variants (S249C and Y375C) compared to controls, indicating that these variants alter the molecular or biochemical function of FGFR3, affecting cell viability. Oncogenic: The evidence suggests that the variants S249C and Y375C contribute to tumor development or progression by enhancing cell viability, which is a characteristic of oncogenic behavior.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
In controls, the number of cells in the G0/G1 phase of the cell cycle progressively increased at confluence, while the number of viable cells decreased. No significant differences in cell cycle profile or viability were
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional
Justification: Functional: The mention of K652E and Y375C variants also suggests alterations in cell cycle profiles, indicating a change in molecular function related to cell cycle dynamics.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
The saturation density of cells expressing K652E FGFR3 was similar to controls and cells expressing wildtype FGFR3 or S249C KD. Therefore, the magnitude of the phenotypic effect was of the order S249C>Y375C>K652E=Wildtyp
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 6
Evidence Type(s): Diagnostic, Functional
Justification: Diagnostic: The passage discusses the relative frequencies of the mutations K652E, S249C, and Y375C in bladder tumors, indicating an association with the disease. Functional: The passage mentions the phenotypic effects of the variants, suggesting that they alter the behavior of cells expressing these mutations compared to controls.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
Next we studied the effects of mutant FGFR3 in normal urothelial cells by expressing S249C, Y375C and K652E FGFR3 in TERT-NHUC. Expression levels were comparable to those observed in the bladder cancer cell line TCC97-7,
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the expression of mutant FGFR3 variants S249C and Y375C alters the saturation density and morphology of normal urothelial cells, indicating a change in molecular or biochemical function. Oncogenic: The expression of the mutant FGFR3 variants is associated with changes in cell behavior, such as increased saturation density and altered morphology, which suggests a contribution to tumor development or progression.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
Initially, we assessed the ability of three mutant forms of FGFR3 that are found in UC (S249C, Y375C, and K652E) to transform NIH-3T3 cells. In these cells, expression of all FGFR3 mutations resulted in a transformed spi
[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 3
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the ability of the FGFR3 mutations (S249C, Y375C, and K652E) to transform NIH-3T3 cells, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage describes how the FGFR3 mutations alter molecular function, specifically through increased phosphorylation of various proteins and changes in cell morphology and proliferation, demonstrating their biochemical activity.
Gene→Variant (gene-first): 2261:K652E 2261:S249C 2261:Y375C
Genes: 2261
Variants: K652E S249C Y375C
The 14 NF1-associated gliomas belonging to the molecular high-grade group did not form a distinct epigenomic cluster but instead aligned with other sporadic reference entities, most frequently high-grade astrocytoma with
[Paragraph-level] PMCID: PMC9468105 Section: RESULTS PassageIndex: 14
Evidence Type(s): Diagnostic, Prognostic
Justification: Diagnostic: The passage discusses the association of the BRAF p.V600E mutation with pleomorphic xanthoastrocytoma, indicating its role in defining or classifying this specific tumor type. Prognostic: The Kaplan-Meier survival analysis mentioned in the passage indicates that patients with NF1-associated gliomas have inferior outcomes, suggesting a correlation between the presence of certain mutations and disease prognosis.
Gene→Variant (gene-first): 673:p.V600E
Genes: 673
Variants: p.V600E
Consistent with an autosomal dominant tumor predisposition syndrome, these gliomas arising in the setting of NF1 developed in patients with a heterozygous germline mutation or deletion involving one of two NF1 alleles (a
[Paragraph-level] PMCID: PMC9468105 Section: RESULTS PassageIndex: 4
Evidence Type(s): Predisposing, Oncogenic
Justification: Predisposing: The passage describes a germline mutation (p.R1276*) associated with an autosomal dominant tumor predisposition syndrome, indicating inherited risk for developing gliomas. Oncogenic: The passage discusses the somatic inactivation of the remaining wild-type NF1 allele, which contributes to tumor development in gliomas, indicating that the variant plays a role in oncogenesis.
Gene→Variant (gene-first): 4763:c.4110 + 2 T > G 4763:p.R1276*
Genes: 4763
Variants: c.4110 + 2 T > G p.R1276*
Colorectal cancer (CRC) manifests after the accumulation of genetic and epigenetic alterations along with tumor microenvironments. MicroRNA (miRNA/miR) molecules have been revealed to serve in critical roles in the progr
[Paragraph-level] PMCID: PMC7068240 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the association of high miR-31 expression with poorer mortality and shorter median survival time in patients with advanced colorectal cancer, indicating a prognostic relationship. Diagnostic: The study evaluates the potential of miRNAs as biomarkers for colorectal cancer, suggesting that the presence of the BRAF V600E mutation can be used to classify tumors based on miR-31 expression levels.
Gene→Variant (gene-first): 673:V600E 673:serine/threonine
Genes: 673
Variants: V600E serine/threonine
SF3B1 mutation is considered a founder clone, however we observed 2 patients in which the mutation arose during disease evolution. The first patient was a 74-year-old man who was diagnosed with MDS-EB with trisomy 8 and
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 24
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the acquisition of the SF3B1 R625C, K700E, and SETBP1 E862K mutations during disease evolution, indicating their role in tumor development and progression in the context of MDS-EB transforming to AML. Functional: The mention of the SF3B1 mutations leading to changes in bone marrow morphology, such as the appearance of ring sideroblasts, suggests that these variants alter molecular or biochemical function related to the disease.
Gene→Variant (gene-first): 26040:E862K 23451:K700E 23451:R625C
Genes: 26040 23451
Variants: E862K K700E R625C
Within the entire MDS cohort, by univariate analysis (Supplementary Table 2), the following parameters were associated with worse outcomes: higher BM blasts percentage; lower hemoglobin, platelet and MCV; prior history o
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 21
Evidence Type(s): Prognostic
Justification: Prognostic: The passage discusses the absence of the SF3B1 K700E mutation as an independent predictor of worse overall survival (OS), indicating a correlation between the variant and disease outcome.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
As a next step, among low-grade MDS (<5% BM blasts and <1% PB blasts) with therapy-related cases excluded, we explored to see if the differences persisted between K700E and non-K700E SF3B1mut MDS groups even after applyi
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 20
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage indicates that K700E SF3B1mut MDS showed a trend for longer overall survival (OS) compared to non-K700E SF3B1mut MDS, suggesting a correlation with disease outcome independent of therapy. Diagnostic: The passage discusses the classification of K700E SF3B1mut MDS in relation to the proposed 2020 IWG-PM criteria, indicating its use in defining or classifying a disease subtype.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Therapy-related MDS cases were distributed equally between K700E and non-K700E groups. Within low-grade MDS (MDS-SLD, MDS-MLD and MDS-RS), we excluded therapy-related MDS cases due to a relatively higher representation o
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 19
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage indicates that K700E SF3B1mut MDS is associated with significantly better overall survival (OS) compared to SF3B1wt MDS, suggesting a correlation with disease outcome independent of therapy. Diagnostic: The mention of K700E in the context of classifying MDS subtypes (e.g., comparing K700E SF3B1mut MDS to non-K700E SF3B1mut MDS) supports its role in defining or classifying a disease or subtype.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Between K700E vs. non-K700E SF3B1mut MDS categories, 9 of 39 (23%) K700E SF3B1mut MDS patients died compared to 4 of 55 (7%; p=0.02) non-K700E patients; findings were similar in low-grade MDS patients (16% vs. 3%, p=0.04
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 18
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the overall survival (OS) rates of K700E SF3B1mut MDS patients compared to non-K700E patients, indicating a correlation with disease outcome independent of therapy. Diagnostic: The mention of K700E SF3B1mut MDS patients in relation to non-K700E patients suggests a classification or association with a specific disease subtype.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Within the MDS-EB categories, compared to SF3B1wt, there were no significant differences in OS of K700E SF3B1mut (median OS, not reached vs. 17 7 month, p=0 355) and non-K700E SF3B1mut (median OS, 20 5 vs. 17 7 months; p
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 17
Evidence Type(s): Prognostic
Justification: Prognostic: The passage discusses overall survival (OS) in relation to the K700E variant, indicating that it correlates with disease outcome independent of therapy.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
The majority of patients in all 3 categories were treated with an HMA: 16/17 (94%) K700E mutated patients; 16/19 (84%) non-K700E mutated patients; and 217/277 (78%) SF3B1wt patients. The treatment details are provided in
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 16
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the overall survival (OS) outcomes of K700E SF3B1mut MDS patients compared to SF3B1wt patients, indicating that the K700E variant correlates with better disease outcomes independent of therapy. Diagnostic: The K700E variant is used to classify and differentiate between SF3B1mut and SF3B1wt MDS patients, indicating its role in defining disease subtypes.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Using rMATS, we identified the five most frequent types of alternative splicing events (alternative 5' splice site, A5SS; alternative 3' splice site, A3SS; mutually exclusive exon, MXE; retained intron, RI and skipped ex
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the impact of the SF3B1 K700E variant on alternative splicing events, indicating that it alters molecular function related to splicing and gene expression. Oncogenic: The SF3B1 K700E variant is associated with mutated myelodysplastic syndromes (MDS), suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Splicing analysis between K700E and non-K700E mutated MDS
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional
Justification: Functional: The passage discusses splicing analysis related to the K700E variant, indicating an alteration in molecular function.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
There were no significant differences in normal vs. complex karyotype. When cytogenetic aberrations were classified using the comprehensive cytogenetic scoring system (CCSS; scores from 0-5), SF3B1mut K700E mutated patie
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 12
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the classification of patients based on the presence of the K700E variant, indicating its association with lower CCSS scores, which suggests a role in defining or classifying a disease subtype. Oncogenic: The mention of the K700E variant in the context of patients with MDS (myelodysplastic syndromes) implies its contribution to tumor development or progression, as it is associated with specific cytogenetic aberrations.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
There was no difference in the median SF3B1 variant allele frequency (VAF) between the 2 groups. The frequency of RUNX1 mutation was significantly higher in non-K700E cases (26% vs. 7 3%, p=0 012), and mutations in BCOR
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 11
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
We compared the clinico-pathologic features of 55 K700E vs. 39 non-K700E treatment naive SF3B1mut MDS patients (Table 2). MDS with SF3B1 K700E mutations had a higher percentage of ring sideroblasts (median 50% vs. 34%; p
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 10
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the clinico-pathologic features of MDS patients with K700E mutations, indicating that these mutations are associated with specific disease characteristics and classifications, such as higher percentages of ring sideroblasts and differences in IPSS-R categories. Oncogenic: The K700E mutation in SF3B1 is implicated in the classification of MDS patients and is associated with specific tumor characteristics, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Comparison between SF3B1 K700E and non-K700E mutated MDS
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 9
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
BM aspirates from all patients underwent NGS analysis with an 81-gene panel at the time of diagnosis. The most frequent SF3B1 mutation, noted in ~60% of all patients, was the hotspot K700E. Among the remaining mutations
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 8
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the frequency of specific mutations, including K666, K700E, and R625, in patients with MDS, indicating their association with the disease and their role in defining the mutational landscape. Oncogenic: The mention of SF3B1 mutations, including K700E, K666, and R625, as frequent mutations in patients with MDS suggests that these somatic variants contribute to tumor development or progression in this context.
Gene→Variant (gene-first): 23451:K666 23451:K700E 23451:R625
Genes: 23451
Variants: K666 K700E R625
Mutational landscape of SF3B1mut MDS (K700E and non-K700E subtypes)
[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 7
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the mutational landscape of SF3B1 mutations, specifically mentioning the K700E subtype, which indicates its role in classifying or defining a disease subtype. Oncogenic: The mention of K700E in the context of SF3B1 mutations suggests its contribution to tumor development or progression, as it is associated with a specific subtype of myelodysplastic syndromes (MDS).
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Myelodysplastic syndromes with SF3B1 mutations are regarded to have a favorable prognosis by both WHO and the International Working Group for Prognostication of MDS (IWG-PM). However, in this article, we show that only M
[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 12
Evidence Type(s): Diagnostic, Prognostic
Justification: Diagnostic: The passage discusses how MDS with SF3B1 K700E mutations can be used to refine sub-classification and risk assessment criteria, indicating its role in defining or classifying a disease subtype. Prognostic: The passage states that MDS with SF3B1 K700E mutations is regarded to have a favorable prognosis, which correlates with disease outcome independent of therapy.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Myelodysplastic syndromes (MDS) with K700E and non-K700E SF3B1 mutations show distinct clinicopathological and genomic characteristics, with only SF3B1 K700E mutated MDS showing a significantly better OS compared to non-
[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 10
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage indicates that SF3B1 K700E mutated MDS shows significantly better overall survival (OS) compared to non-K700E mutations, suggesting a correlation with disease outcome. Diagnostic: The mention of distinct clinicopathological and genomic characteristics associated with K700E and non-K700E SF3B1 mutations implies that the mutation type is used for risk-assessment and classification of MDS.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
Fifty-five (60%) patients carried K700E. Recurrent non-K700E mutations (39, 40%) included R625, H662 and K666. Compared to SF3B1mut-K700E, non-K700E patients had a lower median ANC (1 8 vs. 2 4, p=0 005) and were frequen
[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Diagnostic, Prognostic, Oncogenic
Justification: Diagnostic: The passage discusses the association of K700E and non-K700E mutations with specific patient characteristics and outcomes, indicating their role in classifying patients with MDS. Prognostic: The passage reports on overall survival outcomes associated with SF3B1 mutations, including K700E, indicating that these variants correlate with disease prognosis independent of therapy. Oncogenic: The mention of mutations such as K700E contributing to the classification of MDS and their association with specific patient outcomes suggests a role in tumor development or progression.
Gene→Variant (gene-first): 23451:K666 23451:K700 23451:K700E 23451:R625
Genes: 23451
Variants: K666 K700 K700E R625
We analyzed the clinical-pathologic features and outcomes of a single-institutional series of 94 (19%) SF3B1mut and 415 SF3B1wt treatment-naive MDS patients and explored the differences between K700E and non-K700E.
[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the analysis of clinical-pathologic features and outcomes in MDS patients, specifically exploring differences between K700E and non-K700E variants, indicating a potential role in classification or association with disease characteristics. Oncogenic: The mention of analyzing the clinical-pathologic features of SF3B1mut patients, including K700E, suggests that this variant may contribute to tumor development or progression in the context of MDS.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
SF3B1 mutations (SF3B1mut) in myelodysplastic syndromes (MDS) frequently involve codon K700E and have a favorable prognosis. The prognostic effect of non-K700E SF3B1mut is uncertain.
[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage states that SF3B1 mutations, including K700E, have a favorable prognosis in myelodysplastic syndromes, indicating a correlation with disease outcome. Diagnostic: The mention of SF3B1 mutations in the context of myelodysplastic syndromes suggests that these mutations, including K700E, are used to classify or define the disease.
Gene→Variant (gene-first): 23451:K700E
Genes: 23451
Variants: K700E
PTEN expression loss was found in 18 patients (31.6%, Figure 2a). Thirty-nine patients were positive for PTEN expression, in which 17 (29.8%), 14 (24.6%), and 8 (14%) specimens were weak positive, positive and strong pos
[Paragraph-level] PMCID: PMC3141770 Section: RESULTS PassageIndex: 6
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the H1047R mutation is associated with PTEN loss in patients, suggesting that it contributes to tumor development or progression.
Gene→Variant (gene-first): 5290:H1047R
Genes: 5290
Variants: H1047R
The overall incidence of PIK3CA mutations was 12.3% (7 in 57 samples). The majority of mutations occurred at two hotspots, H1047R (7%, 4 samples) at exon 20 encoding the kinase domain (Figure 1a), and E542K (1.8%, 1 samp
[Paragraph-level] PMCID: PMC3141770 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the incidence of PIK3CA mutations and their occurrence in specific samples, indicating their association with the disease. Oncogenic: The mention of PIK3CA mutations, including E542K and H1047R, suggests their role in tumor development, as they are described as mutations found in tumor samples.
Gene→Variant (gene-first): 5290:E542K 5290:H1047R 5728:T1052A
Genes: 5290 5728
Variants: E542K H1047R T1052A
OS of EGFR-TKI treated patients was similar for 1st and 2nd-line EGFR-TKI treatment. Patients not treated with EGFR-TKI had no benefit in OS. Re-biopsies obtained at progression revealed an EGFR-T790M mutation in 73% (n=
[Paragraph-level] PMCID: PMC5652823 Section: ABSTRACT PassageIndex: 7
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage indicates that patients with the EGFR-T790M mutation responded to the 3rd-generation EGFR-TKI osimertinib, suggesting a correlation between the variant and treatment response. Diagnostic: The EGFR-T790M mutation is mentioned as being revealed in re-biopsies at progression, indicating its role in defining or confirming the presence of a specific disease state in patients treated with EGFR-TKIs.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
BACKGROUND: The BRAF inhibitors vemurafenib and dabrafenib are currently the standard treatment for metastatic melanoma with BRAF V600 mutations. However, given the rarity of noncutaneous melanoma, including acral and mu
[Paragraph-level] PMCID: PMC5122709 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the effectiveness of BRAF inhibitors in patients with metastatic melanoma harboring BRAF V600 mutations, indicating a correlation with treatment response. Diagnostic: The BRAF V600 mutation is used to define and classify patients with metastatic melanoma, as all patients in the study had BRAFV600E mutations.
Gene→Variant (gene-first): 673:V600
Genes: 673
Variants: V600
Mutations previously correlated with response were detected in five tumours, four with exon 19 deletions and one with an exon 21 missense L858R point mutation. Increased gene copy number was observed in thirteen tumours,
[Paragraph-level] PMCID: PMC1952070 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses mutations, including the L858R point mutation, in the context of their correlation with response to treatment, indicating a predictive relationship. Diagnostic: The mention of the L858R mutation as part of a group of mutations previously correlated with response suggests its role in defining or classifying a disease subtype.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
PIK3CA encodes the p110alpha catalytic subunit of the phosphoinositide-3-kinase heterodimer. Upon activation, PI3K phosphorylates phosphatidylinositol-4,5-bisphosphate (PIP2) at the third position, generating PIP3. PIP3
[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 7
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how mutations at amino acids p.Glu542 and p.His1047 increase intracellular AKT phosphorylation, indicating an alteration in molecular function related to AKT activation. Oncogenic: The mention of increased AKT phosphorylation due to the H1047R mutation suggests that this somatic variant contributes to tumor development or progression by promoting cellular processes such as survival and proliferation.
Gene→Variant (gene-first): 5290:H1047R 5290:p.Glu542 5290:p.His1047
Genes: 5290
Variants: H1047R p.Glu542 p.His1047
To provide additional evidence for pathogenic PI3K somatic mutations in macrodactyly, exons 2, 10 and 21 were amplified from DNA extracted from the affected tissue of seven additional unrelated macrodactyly patients as w
[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 6
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses somatic mutations in the PIK3CA gene, specifically mentioning that the E542K, H1047R, and H1047L mutations are known gain-of-function mutations frequently mutated in cancer, indicating their contribution to tumor development or progression. Functional: The passage notes that the mutations E542K and H1047 (both H1047R and H1047L) are located in the helical and kinase domains of the PI3K protein, which are known hotspots for somatic gain-of-function mutations, suggesting that these variants alter the molecular function of the protein.
Gene→Variant (gene-first): 5290:E542K 5290:H1047L 5290:H1047R 5163:R115P 5290:p.Glu542 5290:p.His1047
Genes: 5290 5163
Variants: E542K H1047L H1047R R115P p.Glu542 p.His1047
Additional evidence suggested that the R115P mutation in PIK3CA (PI3K) was a likely candidate for macrodactyly. First, somatic activation of AKT, a downstream target of PI3K, was recently described in patients with Prote
[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The R115P mutation in PIK3CA is suggested as a likely candidate for macrodactyly, indicating its association with a specific disease. Oncogenic: The R115L mutation is annotated in a database of somatic mutations in cancer, suggesting its contribution to tumor development or progression.
Gene→Variant (gene-first): 5290:R115L 5163:R115P 5290:p.Arg115
Genes: 5290 5163
Variants: R115L R115P p.Arg115
NS sequence variants were excluded as disease candidates by their (a) presence in 28 control samples sequenced by our group using a similar method, (b) presence in the exome sequence of the germline sample and (c) presen
[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 4
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the presence of the R115P mutation in PIK3CA in lesional tissue but not in blood, indicating its potential role in defining or confirming a disease state. Oncogenic: The R115P mutation in PIK3CA is described as potentially deleterious and is present in lesional tissue, suggesting it contributes to tumor development or progression.
Gene→Variant (gene-first): 91544:C392G 5163:R115P
Genes: 91544 5163
Variants: C392G R115P
Four additional K-Ras mutations (Leu19Phe (1 out of 106 tumours), Lys117Asn (1 out of 106), Ala146Thr (7 out of 106) and Arg164Gln (1 out of 106)) were identified. Lys117Asn and Ala146Thr had phenotypes similar to the ho
[Paragraph-level] PMCID: PMC2837563 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses K-Ras mutations identified in tumors, indicating that these variants contribute to tumor development or progression, particularly with reference to their phenotypes in the context of cancer. Functional: The passage describes the phenotypic effects of the K-Ras mutations, suggesting that they alter molecular or biochemical function, as evidenced by the comparison of their phenotypes to hotspot mutations and wild-type K-Ras.
Gene→Variant (gene-first): 3845:Ala146Thr 3845:Arg164Gln 3845:Leu19Phe 3845:Lys117Asn
Genes: 3845
Variants: Ala146Thr Arg164Gln Leu19Phe Lys117Asn
We investigated whether the above large-scale patterns characterize all KRAS, HRAS and NRAS hotspot variants, by projecting the amino acid substitutions at G12, G13 and Q61 and observed an overall similar pattern, but wi
[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 20
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how specific amino acid substitutions at G12, G13, and Q61 alter biochemical properties and mechanisms across RAS proteins, indicating a change in molecular function related to GTP hydrolysis and downstream signaling. Oncogenic: The mention of hotspot variants and their clustering patterns suggests that these somatic variants contribute to tumor development or progression, particularly in the context of their distinct biochemical properties and disease incidence.
Gene→Variant (gene-first): 3845:G12 3845:G13 3845:Q61
Genes: 3845
Variants: G12 G13 Q61
To visualize the relative changes in GAP-mediated hydrolysis and RAF affinity across all 935 RAS family variants, we extended PHATE to 2D and followed a similar procedure as above. 2D PHATE for GAP-mediated hydrolysis (F
[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 19
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how different KRAS mutations, including G12C/D and G12D, affect downstream activity and enzyme function, as demonstrated by Western blot analyses measuring pERK levels. Oncogenic: The mention of KRAS hotspot variants and their distinct effects on downstream signaling suggests that these somatic mutations contribute to tumor development or progression.
Gene→Variant (gene-first): 3845:G12 3845:G12C 3845:G12C/D 3845:G12D 3845:G13 3845:Q61
Genes: 3845
Variants: G12 G12C G12C/D G12D G13 Q61
Additionally, we predicted relative RAF affinity changes for amino acid substitutions lacking experimental measurements (15 out of 23; Fig. 4B). These include G12S, which we predict has a decreased RAF affinity like othe
[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 16
Evidence Type(s): Functional, Predictive
Justification: Functional: The passage discusses how specific amino acid substitutions affect RAF affinity, indicating that these variants alter molecular function related to protein interactions. Predictive: The passage predicts changes in RAF affinity for various variants, suggesting a correlation with potential therapeutic responses or resistance based on their affinity levels.
Gene→Variant (gene-first): 3265:A146V 673:A18D 3265:A59T 3845:G12 3845:G12S 3845:G13C 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P
Genes: 3265 673 3845 4893 22882
Variants: A146V A18D A59T G12 G12S G13C G13V K117N L19F Q22K Q61H Q61P Q61R R164Q T74P
We investigated how the 23 KRAS variants change RAF affinity by first identifying the computational scores exhibiting strongest associations with this property (Fig. 4), all of which were from 3D structure and emphasize
[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 15
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the KRAS variants alter RAF affinity, indicating that these variants affect molecular function, specifically in relation to protein interactions and binding properties. Oncogenic: The context of the variants being associated with RAF affinity suggests a role in tumor development or progression, as RAF is a key component in signaling pathways that drive cancer.
Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12C 3845:G12C/D 3845:G12R 3845:G13C/D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H/L 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P 22882:V/A
Genes: 3845 3265 673 4893 22882
Variants: A146T A146V A18D A59T G12C G12C/D G12R G13C/D G13V K117N L19F Q22K Q61H/L Q61P Q61R R164Q T74P V/A
In our second approach, we used PHATE dimensionality reduction to score overall similarities among the 935 variants from 7 RAS genes. We performed 1D PHATE (PHATE1) analysis of the 5 computational scores that correlated
[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 13
Evidence Type(s): Functional, Predictive, Oncogenic
Justification: Functional: The passage discusses how mutated KRAS proteins may alter GAP binding and change GAP-mediated hydrolysis rates, indicating that the variants affect molecular function. Predictive: The analysis provides a probability density distribution and suggests that the variants can predict relative levels for mutations based on their GAP-mediated hydrolysis rates, indicating a correlation with functional outcomes. Oncogenic: The context of the variants being associated with cancer and their effects on GAP-mediated hydrolysis suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12A/R 3845:G12D 3845:G12S 3845:G13C 3845:G13D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 22882:T74P
Genes: 3845 3265 673 22882
Variants: A146T A146V A18D A59T G12A/R G12D G12S G13C G13D G13V K117N L19F Q22K Q61H T74P
In our first approach, we examined patterns among five computational scores (one protein sequence and four 3D structure-based scores) that correlate with the GAP-mediated hydrolysis rate (Fig. 3A and B). All four structu
[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional
Justification: Functional: The passage discusses how mutations, including G13C, A146V, K117N, and G13V, alter local stability and modulate local unfolding, indicating a change in molecular function related to the hydrolysis rate.
Gene→Variant (gene-first): 3265:A146V 3845:G13C 3265:G13V 3845:K117N
Genes: 3265 3845
Variants: A146V G13C G13V K117N
Because genetic variation outside of classic somatic hotspots has received relatively little attention, we next sought to quantify similarities among them by combining information across different experimental measuremen
[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Diagnostic
Justification: Functional: The passage discusses how various KRAS variants, including both hotspot and non-hotspot mutations, exhibit distinct profiles and behaviors based on experimental measurements, indicating that these variants alter molecular or biochemical function. Diagnostic: The mention of clustering variants and their association with specific profiles suggests that these variants can be used to classify or define differences in behavior, which aligns with diagnostic evidence.
Gene→Variant (gene-first): 3845:A146T 3845:A146T/V 3265:A59T 3845:G12A/R 3845:G12A/R/S 3845:G12V/D 3845:G13C 3845:G13V/D 673:K177N 3845:L19F 3845:Q22K 3845:Q61 3845:Q61H 3845:Q61L/P 3845:R164Q 22882:T74P
Genes: 3845 3265 673 22882
Variants: A146T A146T/V A59T G12A/R G12A/R/S G12V/D G13C G13V/D K177N L19F Q22K Q61 Q61H Q61L/P R164Q T74P
We developed a harmonized dataset for rapidly assessing mutational effects on the biochemical properties of the GTPase encoded by KRAS. We collected, processed, and categorized data derived from studying 23 KRAS hotspot
[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 4
Evidence Type(s): Functional
Justification: Functional: The passage discusses how various KRAS variants, including G12, G12V, G13, Q61, and T74, affect biochemical properties such as GTP binding, nucleotide exchange, and hydrolysis, indicating that these variants alter molecular or biochemical function.
Gene→Variant (gene-first): 3845:G12 3845:G12V 3845:G13 3845:Q61 22882:T74
Genes: 3845 22882
Variants: G12 G12V G13 Q61 T74
Stratification analysis was also performed to evaluate the potential effects of TYMS rs3786362 in mCRC patients in the dominant model. Overall, the carriers of the risk G allele reduced PFS with respect to female, younge
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 15
Evidence Type(s): Prognostic, Predictive
Justification: Prognostic: The passage discusses how the rs3786362 variant correlates with progression-free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC) patients, indicating its association with disease outcomes independent of therapy. Predictive: The passage suggests that TYMS rs3786362 could be a predictive biomarker for survival in mCRC patients, indicating a potential correlation with treatment response in specific subgroups.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
Stratification analysis of rs3786362 in TYMS and mCRC survival
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 14
Evidence Type(s): Prognostic
Justification: Prognostic: The passage indicates that rs3786362 is involved in stratification analysis related to mCRC survival, suggesting a correlation with disease outcome.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
In order to explore the correlation of rs3786362 in TYMS and responses to first-line chemotherapy in mCRC patients, we conducted three models including additive model, dominant model and recessive model for correlation a
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the correlation of the variant rs3786362 with responses to first-line chemotherapy in mCRC patients, indicating that the G allele is associated with reduced disease control rate (DCR), which relates to treatment response.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
The correlation between rs3786362 in TYMS and DCR of mCRC patients
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the correlation between the variant rs3786362 and the disease control rate (DCR) in metastatic colorectal cancer (mCRC) patients, indicating a relationship with treatment response.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
Kaplan-Meier curves of PFS and OS for TYMS rs3786362 in mCRC patients were depicted choosing the dominant model. Patients with AG/GG genotypes exhibited reduced PFS and OS compared with AA genotype (Figure 2).
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 11
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the correlation of the rs3786362 variant with progression-free survival (PFS) and overall survival (OS) in mCRC patients, indicating its association with disease outcome independent of therapy. Diagnostic: The variant rs3786362 is used to classify patients based on their genotypes (AG/GG vs. AA), which suggests its role in defining or associating with a disease subtype in mCRC.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
Owing to the positive findings of TYMS rs3786362 on PFS in our previous study, the correlation analysis of the selected SNP with OS was further conducted. Interestingly, TYMS rs3786362 was also associated with reduced OS
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 10
Evidence Type(s): Prognostic, Diagnostic
Justification: Prognostic: The passage discusses the association of the variant rs3786362 with reduced overall survival (OS) and progression-free survival (PFS), indicating its correlation with disease outcomes independent of therapy. Diagnostic: The variant rs3786362 is associated with different genotypes (AG and AA) that correlate with reduced PFS and OS, suggesting its role in classifying disease outcomes based on genotype.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
The correlation between rs3786362 in TYMS and mCRC survival
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 9
Evidence Type(s): Prognostic
Justification: Prognostic: The passage discusses the correlation between the variant rs3786362 and mCRC survival, indicating its association with disease outcome independent of therapy.
Gene→Variant (gene-first): 7298:rs3786362
Genes: 7298
Variants: rs3786362
We analyzed the association between 35 SNPs and PFS of mCRC patients in the additive model after genotyping (Supplementary Table S4). As shown in Table 1, we found that four SNPs (rs369803 in FOLH1, rs10432965 in FTCD, r
[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 8
Evidence Type(s): Prognostic, Predictive
Justification: Prognostic: The passage discusses the correlation of SNPs, specifically rs3786362 and rs369803, with progression-free survival (PFS) in metastatic colorectal cancer (mCRC) patients, indicating their association with disease outcome. Predictive: The passage mentions the correlation of SNPs with disease control rate (DCR), suggesting that these variants may influence treatment response in mCRC patients.
Gene→Variant (gene-first): 10841:rs10432965 2346:rs369803 7298:rs3786362 113235:rs4795436
Genes: 10841 2346 7298 113235
Variants: rs10432965 rs369803 rs3786362 rs4795436
The maximum tolerated dose was established as 40 mg/d; dose-limiting toxicities included reversible thrombocytopenia and nonhematologic toxicity. Across the entire study, the most common grade >= 3 treatment-emergent adv
[Paragraph-level] PMCID: PMC7325368 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the response of patients with B-RAFV600E mutations to therapy, indicating a correlation between the variant and treatment outcomes in various cancers. Diagnostic: The mention of B-RAFV600E in the context of specific cancer types suggests its use as a biomarker to classify or define these diseases.
Gene→Variant (gene-first): 673:B-RAFV600E
Genes: 673
Variants: B-RAFV600E
Lifirafenib is an investigational, reversible inhibitor of B-RAFV600E, wild-type A-RAF, B-RAF, C-RAF, and EGFR. This first-in-human, phase I, dose-escalation/dose-expansion study evaluated the safety, tolerability, and e
[Paragraph-level] PMCID: PMC7325368 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses lifirafenib as an inhibitor specifically targeting B-RAFV600E, indicating a correlation with response to therapy in patients with B-RAF-mutated tumors. Oncogenic: The mention of B-RAFV600E in the context of mutated solid tumors suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 673:B-RAFV600E
Genes: 673
Variants: B-RAFV600E
TNBC cell lines (MDA-MB-231 and MDA-MB-468) with PIK3CA gene mutations (E545K and H1047R regions) and overexpression were established by transfection. NOD/SCID mice were used for in vivo experiments. Epirubicin was used
[Paragraph-level] PMCID: PMC8033310 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses the establishment of TNBC cell lines with PIK3CA gene mutations (E545K and H1047R) and their use in in vivo experiments, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage mentions the use of various assays (e.g., western blot, quantitative reverse transcription-polymerase chain reaction) to detect gene and protein expression levels, suggesting that the variants may alter molecular or biochemical function.
Gene→Variant (gene-first): 5290:E545K 5290:H1047R
Genes: 5290
Variants: E545K H1047R
The distribution pattern of the HER2 insertion mutations observed in our cohort was consistent with prior literature. The HER2 Y772_A775dupYVMA mutation was the most frequent and occurred in 65 (72.2%) patients, of whom
[Paragraph-level] PMCID: PMC8887939 Section: RESULTS PassageIndex: 11
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the overall response rate (ORR) and median progression-free survival (PFS) associated with the HER2 insertion mutations, indicating a correlation with treatment response. Diagnostic: The mention of the frequency of the HER2 Y772_A775dupYVMA mutation in patients suggests its role in defining or classifying a specific disease subtype.
Gene→Variant (gene-first): 2064:A775dupYVMA 2064:G776delinsVC
Genes: 2064
Variants: A775dupYVMA G776delinsVC
KRAS G12D-mutant/p53-deficient non-small-cell lung cancer (NSCLC) models are dependent on the NF-kappaB pathway that can be down-regulated by the proteasome inhibitor bortezomib. Two exceptional responders were observed
[Paragraph-level] PMCID: PMC6549573 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between the KRAS G12D mutation and response to the therapy bortezomib, indicating that exceptional responses can be achieved in patients with this mutation. Oncogenic: The KRAS G12D mutation is described as a somatic variant that contributes to tumor development in non-small-cell lung cancer (NSCLC) models, indicating its role in oncogenesis.
Gene→Variant (gene-first): 3845:G12D
Genes: 3845
Variants: G12D
In the TAS6417 structure, the tricyclic core of the inhibitor forms dual hydrogen bonds to the kinase hinge, and the acrylamide forms the expected covalent bond with C797 (Fig. 4F). The quinoline substituent extends into
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 18
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variant C797 interacts with the inhibitor at a molecular level, specifically forming covalent bonds and influencing the binding interactions within the kinase structure.
Gene→Variant (gene-first): 1956:C797 1956:T790
Genes: 1956
Variants: C797 T790
The core of TAK-788, which is identical to osimertinib, binds in essentially the same manner as osimertinib and the additional isopropyl ester of TAK-788 extends into the back pocket alongside the gatekeeper T790 and sim
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 17
Evidence Type(s): Functional, Predictive
Justification: Functional: The passage discusses how the variant T790 interacts with the drug TAK-788, specifically mentioning hydrogen bonding and binding modes, indicating an alteration in molecular function. Predictive: The mention of TAK-788 binding to T790 suggests a correlation with therapeutic response, as it implies that the presence of T790 may influence the effectiveness of the treatment.
Gene→Variant (gene-first): 1956:T790
Genes: 1956
Variants: T790
Poziotinib is an anilinoquinazoline inhibitor and binds in the manner expected for this compound class, with a single hydrogen bond to the hinge region, and the halogen-substituted aniline group in the back pocket adjace
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 16
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the C797 variant forms a covalent bond with the inhibitor, indicating an alteration in molecular function related to drug binding. Oncogenic: The T790M and V948R variants are described in the context of adopting an inactive kinase conformation, which suggests their role in tumor progression or development.
Gene→Variant (gene-first): 1956:C797 1956:T790M 1956:V948R
Genes: 1956
Variants: C797 T790M V948R
BAY-33 binds with its pyridine group adjacent to the hinge region of the kinase, where it forms a single hydrogen bond with the backbone amide of M793 (Fig. 4 A and B). The fluoro- and methoxy- substituted anilino group
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 15
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:T790
Genes: 1956
Variants: T790
As we have been unable to obtain suitable crystals of the insASV or insSVD variants, we determined cocrystal structures of BAY-33, TAK-788, TAS6417, and poziotinib with WT EGFR to better understand their binding modes an
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 14
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:T790M 1956:V948R
Genes: 1956
Variants: T790M V948R
To better understand the degree of correlation in drug sensitivity across WT and various EGFR mutants, we plotted pairwise comparisons of IC50 values (Fig. 2). This analysis revealed little if any correlation in inhibito
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 9
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the correlation between the L858R variant and drug sensitivity, indicating that the L858R mutation has a drug-sensitizing effect, which aligns with predictive evidence regarding therapy response. Oncogenic: The L858R variant is implicated in greater potency against EGFR compared to WT EGFR, suggesting its role in tumor development or progression, which is characteristic of oncogenic evidence.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
We measured the biochemical potencies of a diverse panel of EGFR inhibitors against insASV, insSVD, and insNPG exon 20 insertion mutants and for comparison against WT EGFR and the L858R and L858R/T790M point mutants. Inh
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the measurement of biochemical potencies of EGFR inhibitors against specific mutants, including L858R and L858R/T790M, indicating a correlation with response to therapy. Functional: The passage describes the use of recombinant EGFR kinase proteins in assays to evaluate the biochemical activity of inhibitors, which implies that the variants may alter molecular function.
Gene→Variant (gene-first): 1956:L858R 1956:T790M
Genes: 1956
Variants: L858R T790M
The enhanced inhibitor sensitivity of EGFR L858R and exon 19 deletions stems, at least in part, from their decreased affinity for ATP compared to the WT EGFR. While the Km, ATP values of insASV and insSVD are higher as c
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the enhanced inhibitor sensitivity of the L858R variant in relation to its decreased affinity for ATP, indicating a correlation with sensitivity to EGFR TKIs, which aligns with predictive evidence. Oncogenic: The passage implies that the L858R variant contributes to oncogenicity, as it discusses the variant's biochemical properties and their relation to tumor development and progression.
Gene→Variant (gene-first): 1956:L858R
Genes: 1956
Variants: L858R
We used a coupled enzyme assay to determine enzyme kinetic parameters for these exon 20 insertions, as well as for WT, L858R, and L858R/T790M EGFR for comparison. This well-established continuous assay employs pyruvate k
[Paragraph-level] PMCID: PMC11551396 Section: RESULTS PassageIndex: 4
Evidence Type(s): Functional
Justification: Functional: The passage discusses enzyme kinetic parameters and catalytic efficiencies of the L858R variant and other variants, indicating that these variants alter molecular function as demonstrated by the enzyme assays.
Gene→Variant (gene-first): 7294:Glu4 1956:L858R 1956:T790M
Genes: 7294 1956
Variants: Glu4 L858R T790M
After transfection, the cells were allowed to grow for 24 h and then lysed. The level of EGFR-mCherry and wild-type and S310F HER2-eGFP in the cell lysate was determined by measuring the fluorescence intensity. After a c
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 11
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the S310F variant of HER2 interacts with EGFR and compares its efficiency to wild-type HER2, indicating an alteration in molecular function.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
Single molecule interaction analysis was performed to determine whether the S310F HER mutant formed a heterodimer with the EGFR. We constructed a bicistronic mammalian expression vector encoding EGFR-mCherry and S310F HE
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 10
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the interaction of the S310F HER2 mutant with EGFR and its altered reactivity to specific antibodies, indicating a change in molecular function. Oncogenic: The S310F HER2 variant is implicated in altered interactions that may contribute to tumor development or progression, as suggested by the context of the study involving cancer-related proteins.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
3.4. Single-Molecular Interaction Analysis Demonstrated That the S310F HER2 Mutant Formed Heterodimers with the EGFR
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 9
Evidence Type(s): Functional
Justification: Functional: The passage indicates that the S310F variant alters the molecular interaction by forming heterodimers with EGFR, suggesting a change in biochemical function.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
We tested the effects of anti-HER2 agents on 5637 cell proliferation and the level of HER2 phosphorylation at Y1221 and Y1222 residues. The cells were incubated with pertuzumab, trastuzumab and lapatinib for 96 h, lysed
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the effects of anti-HER2 agents on cell proliferation and HER2 phosphorylation in relation to the S310F HER2 mutant, indicating a correlation with response to specific therapies. Oncogenic: The S310F variant is implicated in the phosphorylation process and cell proliferation in cancer cells, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
3.3. EGFR Activates S310F HER2 Mutant in 5637 Cell
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage indicates that the S310F variant in HER2 is associated with activation in a cell line, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
To confirm the expression of the S310F HER2 mutant in 5637 cells, we used immunoprecipitation experiments. We hypothesized that if the cells expressed the S310F HER2 mutant, it would not be immunoprecipitated by pertuzum
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 6
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the expression of the S310F HER2 mutant and its interaction with pertuzumab, indicating that the variant alters the molecular function of HER2 in terms of immunoprecipitation. Oncogenic: The S310F variant is described in the context of its expression in cancer cell lines, suggesting that it may contribute to tumor development or progression.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
We searched literatures to identify a human cell line expressing the S310F mutant and found that bladder cancer cell line 5637 expressed the mutant. To test the allelic expression of the S310F HER2 mutant in the 5637 cel
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 5
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the expression and detection of the S310F HER2 mutant in a bladder cancer cell line, indicating that the variant alters the molecular function of the HER2 protein as it is being analyzed for its presence on the cell surface. Oncogenic: The S310F variant is discussed in the context of a bladder cancer cell line, suggesting that it may contribute to tumor development or progression, which aligns with the definition of an oncogenic variant.
Gene→Variant (gene-first): 2064:S310 2064:S310F
Genes: 2064
Variants: S310 S310F
3.2. A Bladder Cancer Cell Line, 5637, Expresses Both Wild-Type HER2 and S310F Mutant
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 4
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
A construct encoding the S310F HER2 extracellular domain fused to a human Fc domain of immunoglobulin heavy chain was prepared and cloned into a mammalian expression vector. For comparison, the expression vectors encodin
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 3
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the binding interactions of various HER2 mutants with the antibodies pertuzumab and trastuzumab, indicating their response to these therapies. Functional: The passage describes the preparation and purification of recombinant fusion proteins and their binding characteristics, which suggests alterations in molecular function related to the HER2 mutants.
Gene→Variant (gene-first): 2064:G309 2064:G309A 2064:G309E 2064:S309A 2064:S310 2064:S310F 2064:S310Y
Genes: 2064
Variants: G309 G309A G309E S309A S310 S310F S310Y
3.1. The Recombinant S310F Mutant Is Not Reactive to Pertuzumab but Binds to Trastuzumab
[Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 2
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage indicates that the S310F mutant is not reactive to Pertuzumab, suggesting a correlation with resistance to this specific therapy. Functional: The passage discusses the binding characteristics of the S310F mutant, indicating an alteration in molecular function related to its interaction with Trastuzumab.
Gene→Variant (gene-first): 2064:S310F
Genes: 2064
Variants: S310F
KIT kinase V559D mutation is the most prevalent primary gain-of-function mutation in Gastrointestinal Stromal Tumors (GISTs). Here we reported a highly selective KIT V559D inhibitor CHMFL-KIT-031, which displayed about 1
[Paragraph-level] PMCID: PMC5762309 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the selective inhibitor CHMFL-KIT-031 and its efficacy against the KIT V559D mutation, indicating a correlation with response to therapy. Oncogenic: The KIT V559D mutation is described as a primary gain-of-function mutation in GISTs, suggesting it contributes to tumor development or progression.
Gene→Variant (gene-first): 3815:D816V 3815:L576P 3815:N822K 3815:T670I 3815:V559D 3815:V654A
Genes: 3815
Variants: D816V L576P N822K T670I V559D V654A
Recent advances in molecular profiling technologies allow genetic driver events in individual tumors to be identified. The hypothesis behind this ongoing molecular profiling effort is that improvement in patients' clinic
[Paragraph-level] PMCID: PMC5002925 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the treatment of a patient with advanced colorectal cancer using trastuzumab based on the presence of the ERBB2 p.L755S mutation, indicating a correlation with therapy response. Oncogenic: The mention of the ERBB2 p.L755S mutation as a genetic driver event in the context of advanced colorectal cancer suggests its role in tumor development or progression.
Gene→Variant (gene-first): 2064:p.L755S 673:p.N581S 324:p.Q1429fs
Genes: 2064 673 324
Variants: p.L755S p.N581S p.Q1429fs
In keeping with the identification of KRAS and/or NRAS mutations as the dominant genomic change associated with treatment resistance, serial ctDNA analysis was able to reveal the emergence of these mutations prior to dis
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 24
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the emergence of KRAS mutations associated with treatment resistance, indicating a correlation with response to therapy, specifically in the context of chemotherapy and targeted treatments. Oncogenic: The passage describes the identification of KRAS mutations that contribute to tumor progression, particularly noting the emergence of these mutations prior to disease progression, which is indicative of their role in cancer development.
Gene→Variant (gene-first): 3791:A163G 3845:G12D 3845:G12N 3845:G13D 3845:Q61H 4893:Q61L 79811:R106H 673:V600E
Genes: 3791 3845 4893 79811 673
Variants: A163G G12D G12N G13D Q61H Q61L R106H V600E
Plasma DNA collected at the time of disease progression was analyzed through targeted sequencing to identify evidence of genomic evolution following treatment and potential mechanisms of acquired resistance to therapy. I
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 23
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses the retention of the BRAF V600E mutation in patients with mCRC, indicating its role in tumor development or progression, particularly in the context of disease progression and treatment response.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
The ratio of BRAF V600E mutation VAF on treatment at week 2 and week 4, relative to baseline was assessed as a predictor of PFS and OS. Most patients (19/21; 91%) had a week 2-baseline ratio (W2-BLR) of <1, with a median
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 20
Evidence Type(s): Prognostic, Predictive
Justification: Prognostic: The passage discusses how the BRAF V600E mutation VAF ratio correlates with progression-free survival (PFS) and overall survival (OS), indicating that it is associated with disease outcomes independent of therapy. Predictive: The assessment of the BRAF V600E mutation VAF ratio as a predictor of PFS and OS suggests that it may correlate with treatment response, indicating its predictive value in the context of therapy.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
We next explored whether early, dynamic changes in ctDNA levels were predictive of outcomes to combination vemurafenib and erlotinib therapy. A total of 25 paired baseline-week 2 (BL-W2) and 21 paired baseline-week 4 (BL
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 19
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how early changes in ctDNA levels, specifically related to the BRAF V600E variant, are predictive of clinical benefit and objective response to combination vemurafenib and erlotinib therapy. Oncogenic: The BRAF V600E variant is implicated in tumor dynamics and is associated with the response to treatment, indicating its role in tumor development or progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
In addition to ddPCR testing, baseline plasma DNA was analyzed using a targeted capture based next-generation sequencing assay (Avenio Expanded panel, Roche Diagnostics; Supplementary Table S1 for list of genes). At leas
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 16
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage indicates that the presence of genetic alterations, including the NRAS G13C mutation, correlates with clinical benefit from treatment, suggesting a predictive relationship regarding therapy response. Diagnostic: The mention of the NRAS G13C mutation being detected in a patient implies its role in identifying or classifying the disease, which aligns with diagnostic evidence. Oncogenic: The NRAS G13C mutation is discussed in the context of being a mutation found in a patient, which suggests its potential role in tumor development or progression.
Gene→Variant (gene-first): 4893:G13C
Genes: 4893
Variants: G13C
Twenty-five patients had serial plasma available for ctDNA analyses (Fig. 3A). Baseline pretreatment plasma DNA analyzed by droplet digital PCR (ddPCR) was positive for BRAF V600E mutant ctDNA in 21 of 25 patients (84%).
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 15
Evidence Type(s): Diagnostic, Prognostic, Oncogenic
Justification: Diagnostic: The passage indicates that BRAF V600E mutant ctDNA is detected in a significant proportion of patients, suggesting its use in defining or confirming the presence of a specific disease. Prognostic: The passage states that higher levels of ctDNA at baseline are associated with inferior progression-free survival (PFS) and overall survival (OS), indicating a correlation with disease outcome independent of therapy. Oncogenic: The presence of the BRAF V600E variant in ctDNA suggests its role in tumor development or progression, as it is a known somatic mutation associated with cancer.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
A total of 40 patients were enrolled across the dose escalation and dose expansion phases (mCRC n = 33 and non-CRC cohort n = 7) between July 2014 and August 2017 (Fig. 1A). The non-colorectal cancer cohort included 7 pa
[Paragraph-level] PMCID: PMC10011885 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage mentions that the non-colorectal cancer cohort included patients who were BRAF V600E mutation positive, indicating that this variant is used to classify or define a specific group of patients with selected cancers. Oncogenic: The BRAF V600E mutation is associated with tumor development in various cancers, as indicated by its presence in patients with selected cancers, suggesting its role in oncogenesis.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
Epidermal growth factor receptor (EGFR) exon 20 insertion mutations account for a tenth of all EGFR mutations in lung cancers. An important unmet clinical need is the identification of EGFR exon 20 insertion mutants that
[Paragraph-level] PMCID: PMC8700411 Section: ABSTRACT PassageIndex: 1
Evidence Type(s): Predictive, Diagnostic, Oncogenic
Justification: Predictive: The passage discusses the sensitivity of specific EGFR variants (D770 and G770) to various EGFR-TKIs, indicating a correlation with response to therapy. Diagnostic: The mention of EGFR exon 20 insertion mutations and their frequency in lung cancer suggests that these variants are used to classify and define a specific subtype of the disease. Oncogenic: The variants D770 and G770 are described as contributing to tumor development, as they are part of the EGFR mutations associated with lung cancer.
Gene→Variant (gene-first): 1956:D770 1956:G770 1956:Y764insFQEA
Genes: 1956
Variants: D770 G770 Y764insFQEA
Although these cases are limited in number and by reporting biases, they provide supporting evidence that EGFR-D770>GY and other exon 20 insertion mutations with G770 equivalence are sensitive to the clinically available
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that the variant G770 and other exon 20 insertion mutations are sensitive to specific EGFR TKIs, suggesting a correlation with treatment response.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
The majority:but not all:of cases that received poziotinib or mobocertinib in this compiled cohort of advanced lung cancers harboring EGFR exon 20 insertion mutations with G770 equivalence had radiographic responses (Tab
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 12
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the correlation between the G770 variant and radiographic responses to therapies (poziotinib and mobocertinib) in advanced lung cancers, indicating its predictive nature regarding treatment response. Diagnostic: The mention of "EGFR exon 20 insertion mutations with G770 equivalence" suggests that the G770 variant is used to classify or define a specific subtype of lung cancer, supporting its role as a diagnostic marker.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
We identified seven reports from the literature and added one case from our institutional cohort that detailed partial clinical-radiographic parameters in patients with metastatic lung cancers harboring EGFR exon 20 inse
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 10
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of patients with metastatic lung cancers harboring EGFR exon 20 insertion mutations, including G770, to various EGFR TKIs, indicating a correlation with treatment response. Oncogenic: The mention of tumors harboring EGFR exon 20 insertion mutations, including G770, suggests that this somatic variant contributes to tumor development or progression in the context of metastatic lung cancers.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
3.3. Clinical Outcomes of Reported Patients with Advanced Lung Cancers Harboring EGFR Exon 20 Insertion Mutations Encompassing G770 Equivalence
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 9
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses patients with advanced lung cancers harboring EGFR Exon 20 insertion mutations, indicating that the variant is used to classify or define a specific disease subtype. Oncogenic: The mention of advanced lung cancers suggests that the G770 variant contributes to tumor development or progression, aligning with the definition of an oncogenic variant.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
Our aforementioned preclinical results confirmed the structural modeling of EGFR-D770>GY (Figure 1A) and led us to speculate that patients with advanced lung cancers harboring EGFR exon 20 insertion mutations with a G770
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 8
Evidence Type(s): Predictive
Justification: Predictive: The passage discusses the potential response of patients with advanced lung cancers harboring the G770 variant to specific therapies, indicating a correlation with treatment response.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
The exquisite sensitivity to 2nd generation EGFR TKIs was confirmed at the biochemical level. In Western blot experiments, the phosphorylated form of EGFR was readily inhibited by 10 nM and higher doses of dacomitinib in
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 7
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the sensitivity of the V769dupASV variant to 2nd generation EGFR TKIs, indicating a correlation with response to therapy. Functional: The variant V769dupASV is shown to alter the biochemical function of EGFR, as evidenced by the differing levels of inhibition of phosphorylated EGFR in response to dacomitinib.
Gene→Variant (gene-first): 1956:V769dupASV
Genes: 1956
Variants: V769dupASV
To highlight the differences in proliferation assays between Ba/F3 cells driven by the EGFR-D770>GY mutant and the more typical EGFR-A767_V769dupASV mutant, we show the dose-response curve for increasing concentrations o
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 6
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the response of cells with the A767_V769dupASV mutant to specific therapies (afatinib and dacomitinib), indicating a correlation between the variant and treatment sensitivity. Oncogenic: The variant A767_V769dupASV is mentioned in the context of proliferation assays, suggesting that it contributes to tumor development or progression in the tested cell lines.
Gene→Variant (gene-first): 1956:V769dupASV
Genes: 1956
Variants: V769dupASV
Our group generated a Ba/F3 cell line driven by the EGFR-D770>GY mutant in order to compare its properties with our previously described isogenic Ba/F3 preclinical models of exon 20 insertion mutants (Figure 2). To evalu
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 5
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the sensitivity and resistance of various EGFR mutations, including D770_N771insSVD, V769dupASV, and Y764insFQEA, to different EGFR TKIs, indicating a correlation with response to therapy. Oncogenic: The variants mentioned are associated with the development of cancer, as they are described in the context of a Ba/F3 cell line model driven by specific EGFR mutations, which contribute to tumor behavior.
Gene→Variant (gene-first): 1956:D770_N771insSVD 1956:V769dupASV 1956:Y764insFQEA
Genes: 1956
Variants: D770_N771insSVD V769dupASV Y764insFQEA
3.2. Preclinical Characterization of an EGFR Exon 20 Insertion Mutant with a G770 Equivalence
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 4
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
We queried three separate cohorts of EGFR exon 20 insertion mutations. Out of the 429 cases reported, 17 (3.96%) had the EGFR mutation leading to G770 equivalent change in the context of an insertion (Figure 1B). The typ
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 3
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses the prevalence of the G770 variant in a cohort of cases with EGFR exon 20 insertion mutations, indicating its association with a specific mutation type and providing context for its classification. Oncogenic: The mention of the G770 variant in the context of EGFR mutations suggests its role in tumor development or progression, as it is part of a known oncogenic pathway associated with cancer.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
3.1. Frequency of EGFR Exon 20 Insertions with a G770 Equivalence
[Paragraph-level] PMCID: PMC8700411 Section: RESULTS PassageIndex: 2
Evidence Type(s): Diagnostic
Justification: Diagnostic: The mention of "frequency" in relation to "EGFR Exon 20 Insertions with a G770 Equivalence" suggests that the variant is being used to classify or define a specific disease or subtype.
Gene→Variant (gene-first): 1956:G770
Genes: 1956
Variants: G770
In addition, the ADx-ARMS identified 2 samples with both 19 del and L858R mutation, 4 with both 19 del and T790M mutation, and 1 with both L858R and L861Q or S768I (The two spots were designed in one tube, we could not d
[Paragraph-level] PMCID: PMC3287118 Section: RESULTS PassageIndex: 7
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 1956:L858R 1956:L861Q 1956:S768I 1956:T790M
Genes: 1956
Variants: L858R L861Q S768I T790M
These updated results confirm the substantial clinical benefit and manageable toxicity of dabrafenib plus trametinib in BRAF V600E-mutant ATC. Dabrafenib plus trametinib notably improved long-term survival and represents
[Paragraph-level] PMCID: PMC9338780 Section: ABSTRACT PassageIndex: 8
Evidence Type(s): Predictive, Prognostic
Justification: Predictive: The passage discusses the clinical benefit of dabrafenib plus trametinib in BRAF V600E-mutant ATC, indicating a correlation with improved treatment response. Prognostic: The mention of improved long-term survival in patients with BRAF V600E-mutant ATC suggests a correlation with disease outcome independent of therapy.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
ROAR (NCT02034110) is an open-label, nonrandomized, phase II basket study evaluating dabrafenib plus trametinib in BRAF V600E-mutant rare cancers. The ATC cohort comprised 36 patients with unresectable or metastatic ATC
[Paragraph-level] PMCID: PMC9338780 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the evaluation of dabrafenib plus trametinib in patients with BRAF V600E-mutant cancers, indicating a correlation with treatment response. Oncogenic: The mention of BRAF V600E in the context of a study for rare cancers suggests that this somatic variant contributes to tumor development or progression.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
Combined therapy with dabrafenib plus trametinib was approved in several countries for treatment of BRAF V600E-mutant anaplastic thyroid cancer (ATC) based on an earlier interim analysis of 23 response-assessable patient
[Paragraph-level] PMCID: PMC9338780 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Diagnostic
Justification: Predictive: The passage discusses the approval of combined therapy with dabrafenib plus trametinib for treatment of BRAF V600E-mutant anaplastic thyroid cancer, indicating a correlation with treatment response. Diagnostic: The mention of BRAF V600E as a specific mutation in anaplastic thyroid cancer suggests its role in defining or classifying the disease subtype.
Gene→Variant (gene-first): 673:V600E
Genes: 673
Variants: V600E
The present results suggested that acquired VOPP1-EGFR fusion gene with T790M potentially serve an additional resistance mechanism to first-generation EGFR tyrosine kinase inhibitors in EGFR-mutated NSCLC. And the presen
[Paragraph-level] PMCID: PMC8727519 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses T790M as a resistance mechanism to first-generation EGFR tyrosine kinase inhibitors, indicating its correlation with treatment response. Oncogenic: The mention of T790M in the context of an acquired resistance mechanism suggests that it contributes to tumor progression in EGFR-mutated NSCLC.
Gene→Variant (gene-first): 1956:T790M
Genes: 1956
Variants: T790M
In this case report, we describe a 69-year-old female who received right lobectomy and was diagnosed with pathological stage IIIA lung adenocarcinoma harboring EGFR L858R. Twenty months later he had recurrent disease in
[Paragraph-level] PMCID: PMC8727519 Section: ABSTRACT PassageIndex: 4
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the T790M variant as a potential resistance mechanism to icotinib treatment, indicating its correlation with treatment response. Oncogenic: The L858R variant is described as being present in a patient with lung adenocarcinoma, suggesting its role in tumor development or progression.
Gene→Variant (gene-first): 1956:L858R 1956:T790M
Genes: 1956
Variants: L858R T790M
Taletrectinib continues to show high and durable overall responses, prolonged PFS, robust activity against intracranial lesions and acquired resistance mutations including G2032R, and a favorable safety profile with a lo
[Paragraph-level] PMCID: PMC11272140 Section: ABSTRACT PassageIndex: 8
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the variant G2032R in the context of acquired resistance mutations and mentions the overall responses and prolonged progression-free survival (PFS) associated with taletrectinib, indicating a correlation with treatment response. Oncogenic: The mention of G2032R as an acquired resistance mutation suggests that it contributes to tumor development or progression, particularly in the context of therapy resistance.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
As of November 2023, 173 patients were enrolled (median age, 55 years; 58% female; 73% never smoked; TKI naive: n = 106; crizotinib pretreated: n = 67). In TKI-naive patients, cORR and intracranial cORR were 91% and 88%,
[Paragraph-level] PMCID: PMC11272140 Section: ABSTRACT PassageIndex: 6
Evidence Type(s): Predictive
Justification: Predictive: The passage indicates that 67% of patients with G2032R mutations responded to treatment, suggesting a correlation between the variant and treatment response.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
Taletrectinib, a highly potent, CNS-active, ROS1 tyrosine kinase inhibitor (TKI), has demonstrated high and durable response rates, high intracranial objective response rate (ORR), prolonged progression-free survival (PF
[Paragraph-level] PMCID: PMC11272140 Section: ABSTRACT PassageIndex: 2
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the activity of taletrectinib against the G2032R variant, highlighting its correlation with high response rates and prolonged progression-free survival, indicating predictive evidence related to therapy response. Oncogenic: The mention of the G2032R variant in the context of ROS1+ non-small cell lung cancer suggests that it may contribute to tumor development or progression, aligning with oncogenic evidence.
Gene→Variant (gene-first): 6098:G2032R
Genes: 6098
Variants: G2032R
Some of the differences between the effects of tested inhibitors on activating FGFR variants (Figure 6) are consistent with observations from structural studies. Based on the crystal structure of FGFR1 KD V561M, the inte
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 33
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the expected efficacy of the JNJ42756493 inhibitor towards the FGFR3 V555M variant, indicating a correlation with response to therapy based on structural interactions. Functional: The passage mentions the interactions of inhibitors within the ATP-binding pocket of the FGFR1 KD V561M variant, suggesting that the variant alters molecular function related to drug binding and efficacy.
Gene→Variant (gene-first): 2261:V555M 2260:V561M
Genes: 2261 2260
Variants: V555M V561M
We further compared the effect of the two most potent FGFR-specific inhibitors AZD4547 and JNJ42756493 on hotspot mutations K650E and N540K in NIH3T3 cell lines. As previously reported and shown in Supplementary Figure S
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 32
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses the effect of the K650E and N540K variants on the efficacy of FGFR-specific inhibitors, indicating a correlation with treatment response. Oncogenic: The variants K650E and N540K are discussed in the context of their impact on cellular transformation and response to inhibitors, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 2261:K650E 2261:N540K
Genes: 2261
Variants: K650E N540K
The impact of each mutation on drug binding is expressed as a fold-difference in Ki compared to the FGFR3 KD WT (Figure 6C). Highly activating R669G and, in particular, hotspot mutation K650E had moderate effects on the
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 31
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses how specific mutations, such as K650E, N540K, N540S, and V555M, affect the efficacy of various inhibitors, indicating a correlation with resistance or sensitivity to therapy. Functional: The passage describes how mutations like I538V and V555M alter the binding affinity and efficacy of inhibitors, which reflects changes in molecular function related to drug interactions.
Gene→Variant (gene-first): 2263:I538 2263:I538V 2261:K650E 2261:N540 2261:N540K 2261:N540S 2261:R669G 2261:V555M
Genes: 2263 2261
Variants: I538 I538V K650E N540 N540K N540S R669G V555M
We performed measurements of Ki for AZD4547, BGJ-398, TKI258, JNJ42756493 and AP24534 using purified FGFR3 KD WT and variants R669G, K650E, N540S, N540K, V555M and I538V (Figure 6, Supplementary Table S3). Ki values for
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 30
Evidence Type(s): Predictive, Functional
Justification: Predictive: The passage discusses the Ki values of various FGFR3 variants in response to specific inhibitors, indicating a correlation between the variants and their sensitivity to therapy. Functional: The mention of mutations affecting the ATP binding pocket and potential allosteric effects suggests that these variants alter the molecular function of the FGFR3 protein.
Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:N540K 2261:N540S 2261:R669G 2261:V555M
Genes: 2263 2261
Variants: I538V K650E N540K N540S R669G V555M
It is well established that some acquired mutations in protein kinases greatly reduce drug binding; the best-illustrated examples are gatekeeper mutations also described in FGFR3 (V555M). The question of how primary muta
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 29
Evidence Type(s): Predictive, Oncogenic
Justification: Predictive: The passage discusses how mutations in protein kinases, such as V555M, can affect drug binding and implies a relationship between these mutations and drug efficacy, indicating a potential impact on treatment response. Oncogenic: The mention of V555M as an acquired mutation in FGFR3 suggests its role in tumor development or progression, particularly in the context of drug resistance.
Gene→Variant (gene-first): 2261:V555M
Genes: 2261
Variants: V555M
JNJ42756493 occupies the ATP-binding cleft of FGFR1 largely as expected on the basis of previous complexes between FGFR1 and other type-I inhibitors (e. g. BJG-398, AZD4547, PD173074 and TKI258) and where the activation
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 27
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the variants D641, L630, and V561 are involved in the binding interactions of the drug JNJ42756493 with FGFR1, indicating that these variants alter molecular interactions and contribute to the binding strength and specificity of the drug.
Gene→Variant (gene-first): 2260:D641 2260:L630 2260:V561
Genes: 2260
Variants: D641 L630 V561
Previous structural studies of FGFR2 KD highlighted a long-range allosteric communication linking the kinase hinge, the alphaC-helix and the A-loop. It was also illustrated that some A-loop mutations (such as FGFR3 K650E
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 24
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the K650E, R675G, and R669G mutations alter the allosteric communication and molecular interactions within the FGFR kinases, indicating a change in molecular function. Oncogenic: The mention of mutations that force an active conformation and alter the position of the alphaC-helix suggests that these variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2261:K650E 2261:R669G 2260:R675 2260:R675G
Genes: 2261 2260
Variants: K650E R669G R675 R675G
To gain further insight into the activation mechanism of the R669G mutation in FGFR3, we performed NMR studies in which we compared the backbone amide chemical shift perturbations (CSPs) associated with the R669G mutatio
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 23
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the R669G mutation alters molecular interactions and conformational changes in the FGFR3 protein, indicating an alteration in biochemical function.
Gene→Variant (gene-first): 2261:R669G
Genes: 2261
Variants: R669G
Comparison of this new FGFR1 R675G KD structure (Figure 4C, top) with inactive (apo) FGFR1 KD (PDB: 4UWY) and active, FGFR1-3P (pdb 3GQI) (Figure 4C, bottom) structures shows that FGFR1 R675G KD differs from the inactive
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 22
Evidence Type(s): Functional
Justification: Functional: The passage describes how the R675G variant alters the molecular interactions and conformation of the FGFR1 kinase domain, indicating a change in biochemical function.
Gene→Variant (gene-first): 2261:H650 2260:R675 2260:R675G 2263:Y653
Genes: 2261 2260 2263
Variants: H650 R675 R675G Y653
The residue corresponding to R669 in FGFR3 is conserved and also mutated in all other FGFRs in cancer as well as in FGFR2 in bone dysplasia (Supplementary Table S1). To assess the mechanism that underpins activation, we
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 21
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the R to G replacement and its impact on the activity of the FGFR1 KD variant, indicating that the variant alters molecular function. Oncogenic: The mention of the R669 and R675G variants being mutated in cancer suggests their contribution to tumor development or progression.
Gene→Variant (gene-first): 2260:R to G 2261:R669 2260:R675G
Genes: 2260 2261
Variants: R to G R669 R675G
Activation mechanism of FGFR3 R669G mutation
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 20
Evidence Type(s): Functional
Justification: Functional: The passage discusses the activation mechanism of the FGFR3 R669G mutation, indicating that it alters molecular or biochemical function.
Gene→Variant (gene-first): 2261:R669G
Genes: 2261
Variants: R669G
Comparison of our experimental data (Figure 2) with the assessments obtained using bioinformatics tools (Supplementary Table S1B and S1C) suggests that considering multiple methods together can provide insight into the i
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 19
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the variants E466K, D617G, and G637W are predicted to reduce protein production or completely inactivate the kinase, indicating an alteration in molecular function. Oncogenic: The mention of R669 being within an identified cluster of observed A-loop cancer mutations suggests that it contributes to tumor development or progression.
Gene→Variant (gene-first): 2261:D617G 2263:E466K 2260:G637W 2261:R669
Genes: 2261 2263 2260
Variants: D617G E466K G637W R669
Analysis of the FGFR3 R669G NIH3T3 cell line has shown that despite low expression levels, downstream signaling appeared to be enhanced as well as FGFR3 phosphorylation (Figure 4A).
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 18
Evidence Type(s): Functional
Justification: Functional: The passage discusses how the R669G variant alters downstream signaling and FGFR3 phosphorylation, indicating a change in molecular function.
Gene→Variant (gene-first): 2261:R669G
Genes: 2261
Variants: R669G
It could be expected that some mutations that map to the KD do not affect kinase activity directly as measured under conditions in vitro. In particular, the hotspot G697C mutation which does not have an effect in such as
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 17
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the G697C mutation does not affect kinase activity directly as measured in vitro, indicating that it alters molecular function, specifically FGFR3 function, which can only be detected in a cellular setting. Oncogenic: The comparison of the FGFR3 G697C cell line with those expressing K650E and N540K shows that G697C does not lead to a transformed phenotype or anchorage-independent growth, suggesting it does not contribute to tumor development or progression like the other variants.
Gene→Variant (gene-first): 2261:G697C 2261:K650E 2261:N540K
Genes: 2261
Variants: G697C K650E N540K
From these direct measurements of kinase activity it seems that a considerable number of mutations reported so far result in kinase activation to some degree and that replacements that cause activation are not limited to
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 16
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the K650E variant alters kinase activity, indicating a change in molecular function related to activation. Oncogenic: The mention of the K650E variant in the context of kinase activation suggests its potential role in tumor development or progression.
Gene→Variant (gene-first): 2261:K650E
Genes: 2261
Variants: K650E
Two mutations, D617G and G637W, completely abolished kinase activity (Figure 2A and 2B, bottom panel). Both residues are strongly conserved among protein kinases and some of the replacements of these residues in various
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 15
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how the mutations D617G and G637W abolish kinase activity, indicating that these variants alter the molecular function of the protein. Oncogenic: The passage mentions that the importance of these inactivating mutations for cancer development remains unclear, suggesting a potential role in tumor development or progression.
Gene→Variant (gene-first): 2261:D617 2261:D617G 2261:G to W 2260:G637 2260:G637W
Genes: 2261 2260
Variants: D617 D617G G to W G637 G637W
Twelve out of 26 analyzed mutations had very little or no effect on FGFR3 KD activity (Figure 2A and 2B, bottom panel). The number of observations in cancer for most of these mutations is low with the exception of G697C
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 14
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses the effect of the G697C mutation on FGFR3 KD activity, indicating that it alters molecular function. Oncogenic: The mention of G697C as one of the hotspots suggests its potential role in tumor development or progression, which aligns with oncogenic behavior.
Gene→Variant (gene-first): 2261:G697C
Genes: 2261
Variants: G697C
Several other mutations, including V555M, D641G and D641N resulted in an increase of auto-phosphorylation up to 7-fold (Figure 2A) and a similar increase in substrate phosphorylation (Figure 2B, middle panel). The V555M
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 13
Evidence Type(s): Predictive, Functional
Justification: Predictive: The V555M mutation is described as an acquired resistance mutation to an FGFR inhibitor, indicating a correlation with resistance to therapy. Functional: The passage discusses how the mutations, including V555M, D641G, and D641N, resulted in an increase in auto-phosphorylation and substrate phosphorylation, indicating an alteration in molecular function.
Gene→Variant (gene-first): 2260:D641G 2260:D641N 2261:V555 2261:V555M
Genes: 2260 2261
Variants: D641G D641N V555 V555M
Isolated FGFR KDs undergo auto-phosphorylation on several tyrosine residues and this property correlates well with the kinase activity towards natural and synthetic substrates. We used purified proteins of 26 FGFR3 KD va
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 12
Evidence Type(s): Functional, Oncogenic
Justification: Functional: The passage discusses how different mutations in FGFR3 KD variants affect auto-phosphorylation and kinase activity, indicating that these variants alter molecular function. Oncogenic: The context of the passage suggests that the mutations contribute to tumor development or progression by enhancing kinase activity, which is a characteristic of oncogenic variants.
Gene→Variant (gene-first): 2263:I538V 2261:K650E 2261:K650N 2261:N540K 2261:N540S 2261:R669G 2261:R669Q
Genes: 2263 2261
Variants: I538V K650E K650N N540K N540S R669G R669Q
The number of cancer mutations in FGFR KDs that have been comprehensively assessed for their functional impact is limited, with the most emphasis being on replacements at positions corresponding to FGFR3 K650 and mutatio
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 11
Evidence Type(s): Functional
Justification: Functional: The passage discusses the functional impact of mutations at positions FGFR3 K650 and N540K, indicating that these variants are assessed for their effect on kinase activity.
Gene→Variant (gene-first): 2261:K650 2261:N540K
Genes: 2261
Variants: K650 N540K
A number of crystal structures of FGFR KD in non-phosphorylated and phosphorylated forms have been reported. The 3D-structures highlighted the features that undergo substantial changes and play a key role in the activati
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 7
Evidence Type(s): Oncogenic
Justification: Oncogenic: The passage discusses FGFR3 cancer mutations, indicating that the variants K650, R669, N540, and I538 are associated with cancer, suggesting their role in tumor development or progression.
Gene→Variant (gene-first): 2263:I538 2261:K650 2261:N540 2261:R669
Genes: 2263 2261
Variants: I538 K650 N540 R669
Comparison of positions mutated in bone dysplasia in all FGFRs with those reported for FGFR3 in cancer (Figure 1B, bottom) highlighted common residues including I538, N540, K650 and R669. With respect to the secondary st
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 6
Evidence Type(s): None
Justification: Not enough information in this passage.
Gene→Variant (gene-first): 2261:G697 2263:I538 2261:K650 2261:N540 2261:R669
Genes: 2261 2263
Variants: G697 I538 K650 N540 R669
It has been previously highlighted that a number of cancer mutations, in particular in FGFR2 and FGFR3, have also been described in various developmental syndromes such as bone dysplasia. Positions mutated in FGFR3 in th
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 5
Evidence Type(s): Diagnostic, Oncogenic
Justification: Diagnostic: The passage discusses mutations in FGFR3, including K650 and N540, in the context of developmental syndromes such as bone dysplasia, indicating their association with specific disease states. Oncogenic: The mention of FGFR3 mutations, including K650 and N540, being prevalent in bladder cancer suggests that these somatic variants contribute to tumor development or progression.
Gene→Variant (gene-first): 2261:K650 2261:N540 2261:N540K
Genes: 2261
Variants: K650 N540 N540K
The intracellular portion (residues 397-806 for FGFR3) comprises the juxtamembrane region, KD and C-terminal regions. The number of observed mutations at each residue within the intracellular portion of FGFR3 was compile
[Paragraph-level] PMCID: PMC5029699 Section: RESULTS PassageIndex: 4
Evidence Type(s): Oncogenic, Functional
Justification: Oncogenic: The passage discusses frequently mutated positions in FGFR3, specifically K650, G697, and N540, indicating their involvement in cancer, which suggests they contribute to tumor development or progression. Functional: The passage describes the specific amino acid replacements at the mutated positions, indicating alterations in molecular function related to FGFR3, which can affect its activity in cancer.
Gene→Variant (gene-first): 2261:G697 2261:G697C 2261:K650 2261:N540
Genes: 2261
Variants: G697 G697C K650 N540