[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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*

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[Paragraph-level] PMCID: PMC7325368 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Diagnostic, Oncogenic

Justification: Predictive: The passage discusses the confirmed responses and stable disease (SD) in patients with K-RAS mutations, including G13D, indicating a correlation with treatment response. Diagnostic: The mention of K-RAS mutations, including G13D, in the context of specific cancer types (endometrial cancer and NSCLC) suggests its role in classifying or defining these diseases. Oncogenic: The reference to K-RAS mutations, including G13D, contributing to tumor development in specific cancer types supports the classification of this variant as oncogenic.

Gene→Variant (gene-first): 3845:G13D

Genes: 3845

Variants: G13D

[Paragraph-level] PMCID: PMC7325368 Section: RESULTS PassageIndex: 10

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the responses of patients with B-RAF mutations to therapy, indicating a correlation between the B-RAFV600E variant and treatment response, which is characteristic of predictive evidence. Oncogenic: The B-RAFV600E variant is mentioned in the context of patients with B-RAF-mutated tumors, suggesting its role in tumor development or progression, which aligns with oncogenic evidence.

Gene→Variant (gene-first): 673:B-RAFV600E

Genes: 673

Variants: B-RAFV600E

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[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

[Paragraph-level] PMCID: PMC3244026 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Diagnostic

Justification: Functional: The passage discusses how the ETV6 mutants (V345fs, N356fs, Y103fs, S105fs) are functionally inactive and lack transcriptional repression activity, indicating that these variants alter molecular function. Diagnostic: The passage mentions that ETV6-mutated cases have a characteristic gene expression signature and that all ETV6 mutant T-ALL samples were CD33 positive, suggesting that these variants are associated with a specific disease subtype.

Gene→Variant (gene-first): 2120:N356fs 2120:S105fs 2120:V345fs 2120:Y103fs

Genes: 2120

Variants: N356fs S105fs V345fs Y103fs

[Paragraph-level] PMCID: PMC3244026 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage describes how N-terminal and C-terminal truncating mutations in the ETV6 gene alter the expression of truncated protein products, indicating a change in molecular function. Oncogenic: The context of the mutations being associated with hematopoietic tumors suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 2120:N356fs 2120:S105fs 2120:V345fs 2120:Y103fs

Genes: 2120

Variants: N356fs S105fs V345fs Y103fs

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage describes the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant as a somatic variant found in renal cell carcinomas (RCCs) and indicates its role in VHL-independent renal tumorigenesis, supporting its contribution to tumor development. Diagnostic: The passage discusses the search for germline ELOC variants in individuals with a VHL-like phenotype and indicates that the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant was absent in these individuals, suggesting its potential use in defining or excluding a disease or subtype.

Gene→Variant (gene-first): 3091:c.236A>G 6921:c.261_272del 5979:c.274G>A 6921:c.311T>A 3855:c.74A>T 3855:p.Asp25Val 7409:p.Glu92Lys 6921:p.Leu104Gln 6921:p.Thr88_Pro91del 3091:p.Tyr79Cys

Genes: 3091 6921 5979 3855 7409

Variants: c.236A>G c.261_272del c.274G>A c.311T>A c.74A>T p.Asp25Val p.Glu92Lys p.Leu104Gln p.Thr88_Pro91del p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 8

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 6

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 3091:236A>G 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: 236A>G c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC9402235 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the identification of a de novo missense variant in ELOC and its validation in the proband, indicating its potential role in defining or confirming a genetic condition. Functional: The passage describes the critical role of the Tyr79 residue in forming a hydrogen bond within the pVHL alpha domain, suggesting that the variant alters molecular function.

Gene→Variant (gene-first): 3091:Tyr79 3091:Y79 3091:c.236A>G 3091:p.Tyr79Cys

Genes: 3091

Variants: Tyr79 Y79 c.236A>G p.Tyr79Cys

[Paragraph-level] PMCID: PMC6594036 Section: RESULTS PassageIndex: 8

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 7010:2690A > G 3845:Arg918Cys 7010:Tyr897Cys 7010:c.2752A > G

Genes: 7010 3845

Variants: 2690A > G Arg918Cys Tyr897Cys c.2752A > G