[Paper-level Aggregated] PMCID: PMC4741605

Evidence Type(s): Oncogenic, Prognostic, Predictive

Justification: Oncogenic: The presence of mutations D835Y, D839G, and D835H in FLT3 is associated with resistance to treatment and disease progression, indicating their role in oncogenesis. Prognostic: The mutations D835Y and D839G are linked to the patient's response to therapy and the likelihood of relapse, suggesting they can provide prognostic information regarding disease outcome. Predictive: The mutations D835Y, D839G, and D835H are associated with resistance to Sorafenib treatment, indicating their potential to predict treatment response.

Gene→Variant (gene-first): FLT3(2322):D835H FLT3(2322):D839G FLT3(2322):D835Y

Genes: FLT3(2322)

Variants: D835H D839G D835Y

[Paper-level Aggregated] PMCID: PMC4695055

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The presence of the c.3082+811A TTTTAACA > GGTTTGAT mutation in the intron 14 region of the MET gene, along with the confirmation of METex14del cases, suggests a role in cancer development, indicating its potential oncogenic nature. Functional: The mention of qualitative RT-PCR and deep sequencing indicates that the mutation may have functional implications in the context of gene expression and potential alterations in the MET gene's activity.

Gene→Variant (gene-first): TP53(7157):c.3082+811A TTTTAACA > GGTTTGAT

Genes: TP53(7157)

Variants: c.3082+811A TTTTAACA > GGTTTGAT

[Paper-level Aggregated] PMCID: PMC4675689

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The D835 mutations are reported to cause FLT3 TKI resistance in patients, indicating their role in tumorigenesis and cancer progression. Predictive: The study suggests that specific D835 mutations can predict the level of resistance to type II FLT3 inhibitors, which can inform treatment decisions. Functional: The text discusses the functional implications of D835 mutations on the stability of the DFG-out conformation and their impact on inhibitor binding, demonstrating the functional consequences of these mutations.

Gene→Variant (gene-first): FLT3(2322):D835 FLT3(2322):D835A/E FLT3(2322):D835H FLT3(2322):D835V/Y FLT3(2322):D835E/N FLT3(2322):D835N/E FLT3(2322):D835Y/V

Genes: FLT3(2322)

Variants: D835 D835A/E D835H D835V/Y D835E/N D835N/E D835Y/V

[Paper-level Aggregated] PMCID: PMC4654747

Evidence Type(s): Oncogenic, Prognostic, Functional

Justification: Oncogenic: The study indicates that mutations in histone H3, specifically K27M and K27I, drive distinct oncogenic programs in DIPG, with H3.3-K27M mutations leading to a proneural/oligodendroglial phenotype and a pro-metastatic gene expression signature. Prognostic: The findings demonstrate that patients with H3.1-K27M mutations have a better overall survival and clinical response to radiotherapy compared to those with H3.3-K27M mutations, indicating that the type of histone mutation is a significant prognostic factor. Functional: The study assesses the functional impact of histone mutations on gene expression profiles and tumor behavior, showing that specific mutations lead to alterations in trimethylation and gene expression that influence tumor characteristics and patient outcomes.

Gene→Variant (gene-first): TP53(7157):83A>T MYCN(4613):84G>T H3-3B(3021):K27I H3-3B(3021):K27M H3C14(126961):lysine-to-isoleucine TLX2(3196):G34R/V H3-3B(3021):lysine 27

Genes: TP53(7157) MYCN(4613) H3-3B(3021) H3C14(126961) TLX2(3196)

Variants: 83A>T 84G>T K27I K27M lysine-to-isoleucine G34R/V lysine 27

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 14

Evidence Type(s): Diagnostic, Prognostic, Oncogenic

Justification: Diagnostic: The passage discusses the association of H3.1-K27M tumors with clinical characteristics and outcomes, indicating its role in defining and classifying the disease. Prognostic: The variant K27M is correlated with overall survival outcomes, with H3.1 mutations showing a better prognosis compared to H3.3 mutations, independent of therapy. Oncogenic: The mention of H3.1-K27M tumors suggests that this somatic variant contributes to tumor development or progression, as it is associated with clinical characteristics and outcomes in cancer patients.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 13

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The K27M mutation is associated with disease behavior, indicating a correlation with disease outcome, specifically suggesting a less aggressive behavior in DIPG. Diagnostic: The mention of the K27M mutation being associated with DIPG suggests its role in defining or classifying this specific disease subtype.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 11

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the strong enrichment of the K27M variant in specific tumor subtypes, indicating its association with the proneural-glioblastoma multiforme (GBM) and oligodendrocytic or neural signatures, which helps classify the disease. Oncogenic: The K27M variant is implicated in tumor development, as evidenced by its association with oligodendroglial differentiation and the observation of metastatic relapse in patients with H3F3A mutations, suggesting a role in tumor progression.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that K27M mutations in H3.3 and H3.1 contribute to distinct oncogenic programs, suggesting their role in tumor development or progression.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 9

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the exclusive presence of the K27M variant in specific tumor subgroups (H3.1-K27M and H3.3-K27M), indicating its role in classifying these tumors. Oncogenic: The K27M variant is associated with specific tumor subgroups and is implicated in tumor development, as indicated by its exclusive presence in H3.1 and H3.3 tumors.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of specific mutations (H3.3-K27M, H3-G34R/V, H3.1- and H3.2-K27M, H3.3 K27I) in different tumor locations, indicating their association with specific tumor types, which supports their use in defining or classifying disease subtypes. Oncogenic: The mention of mutations being identified in specific tumor types suggests that these variants contribute to tumor development or progression, indicating their oncogenic potential.

Gene→Variant (gene-first): 3196:G34R/V 3021:K27I 3021:K27M

Genes: 3196 3021

Variants: G34R/V K27I K27M

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the detection of H3-K27M mutations and their association with immunohistochemistry (IHC) staining, indicating the use of these variants to classify or define a subtype of disease. Functional: The passage mentions the loss of H3K27me3 immunoexpression associated with the K27I variant, indicating an alteration in molecular function related to protein activity or modification.

Gene→Variant (gene-first): 7157:83A>T 4613:84G>T 3021:K27I 3021:K27M 126961:lysine-to-isoleucine

Genes: 7157 4613 3021 126961

Variants: 83A>T 84G>T K27I K27M lysine-to-isoleucine

[Paragraph-level] PMCID: PMC4654747 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the correlation of the H3-K27M mutation with the classification of DIPG samples, indicating its role in defining or confirming the disease subtype. Oncogenic: The mention of the H3-K27M mutation in the context of tumor samples suggests that it contributes to tumor development or progression, characteristic of oncogenic variants.

Gene→Variant (gene-first): 3021:K27M 3021:lysine 27

Genes: 3021

Variants: K27M lysine 27

[Paper-level Aggregated] PMCID: PMC4477877

Evidence Type(s): Predisposing, Functional, Oncogenic

Justification: Predisposing: The identification of germline ETV6 mutations, such as L349P and N385fs, in kindreds affected by thrombocytopenia and acute lymphoblastic leukemia (ALL) suggests a hereditary predisposition to leukemia. Functional: The study demonstrates that the ETV6 mutations impair nuclear localization and transcriptional regulation of ETV6 target genes, indicating a functional impact on the protein's ability to perform its role as a transcription factor. Oncogenic: The presence of ETV6 mutations in individuals with ALL and their association with leukemic phenotypes suggest that these mutations may contribute to oncogenesis in the context of leukemia.

Gene→Variant (gene-first): ETV6(2120):11905459G>A ETV6(2120):12022436 G>A ETV6(2120):R181H ETV6(2120):V37M ETV6(2120):rs150089916 IKZF1(10320):415 T>C ETV6(2120):L349P ETV6(2120):c. T1046C ETV6(2120):proline for leucine at codon 349 ETV6(2120):N385fs ETV6(2120):P214L ETV6(2120):R369Q ETV6(2120):R399C ETV6(2120):c.1153-5_1153_1delAACAG ETV6(2120):p. L349P ETV6(2120):p. N385fs

Genes: ETV6(2120) IKZF1(10320)

Variants: 11905459G>A 12022436 G>A R181H V37M rs150089916 415 T>C L349P c. T1046C proline for leucine at codon 349 N385fs P214L R369Q R399C c.1153-5_1153_1delAACAG p. L349P p. N385fs

[Paper-level Aggregated] PMCID: PMC4411002

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The presence of PIK3CA mutations, specifically c.241 G>A [p.E81K], c.3140 A>G [p.H1047R], and c.3140 A>T [p.H1047L], in patients with a clinical diagnosis of FAO suggests a role in tumorigenesis, as these mutations are associated with cancer-related pathways. Functional: The identification of specific mutations in PIK3CA and their varying frequencies in different tissue types indicates that these mutations may affect the function of the protein, contributing to the disease phenotype observed in the patients.

Gene→Variant (gene-first): PIK3CG(5294):3140 A>T PIK3CA(5290):c.3140 A>G PIK3CA(5290):c.3140 A>T PIK3CA(5290):p.H1047L PIK3CA(5290):p.H1047R PIK3CA(5290):c.241 G>A PIK3CA(5290):p.E81K

Genes: PIK3CG(5294) PIK3CA(5290)

Variants: 3140 A>T c.3140 A>G c.3140 A>T p.H1047L p.H1047R c.241 G>A p.E81K

[Paper-level Aggregated] PMCID: PMC4398541

Evidence Type(s): Functional, Oncogenic, Predictive

Justification: Functional: The text describes a functional analysis of various PTEN mutations, assessing their impact on subcellular localization and PIP3 phosphatase activity, indicating their functional roles in PTEN's tumor suppressor activity. Oncogenic: The mutations are associated with tumorigenesis, as they are described as "tumor-associated" and their effects on PTEN function suggest a potential role in cancer development. Predictive: The analysis of specific mutations and their effects on PTEN activity and localization can predict the functional consequences of these mutations in a clinical context, potentially guiding therapeutic decisions.

Gene→Variant (gene-first): PTEN(5728):A34D PTEN(5728):A34V PTEN(5728):D24Y PTEN(5728):G36R PTEN(5728):I33S PTEN(5728):K13E PTEN(5728):L23F PTEN(5728):L42P PTEN(5728):M35R PTEN(5728):R15I PTEN(5728):R15S PTEN(5728):S10N PTEN(5728):Y16C PTEN(5728):A39V PTEN(5728):Ala residues were mutated to Val ACTG1(71):D19A PTEN(5728):D24A PTEN(5728):E18A PTEN(5728):F21A PTEN(5728):G20A PTEN(5728):I28A PTEN(5728):I32A PTEN(5728):I33A PTEN(5728):K13A PTEN(5728):L42A PTEN(5728):M35A PTEN(5728):N12A PTEN(5728):N31A PTEN(5728):P30A AAA1(100329167):R14A PTEN(5728):R15A PTEN(5728):Y16A PTEN(5728):Y27A PTEN(5728):I5A PTEN(5728):K6A PTEN(5728):P38A PTEN(5728):Q17A PTEN(5728):S10A AAA1(100329167):Arg14 PTEN(5728):Arg15 PTEN(5728):K13R PTEN(5728):Lys13 AAA1(100329167):R14K PTEN(5728):R15K

Genes: PTEN(5728) ACTG1(71) AAA1(100329167)

Variants: A34D A34V D24Y G36R I33S K13E L23F L42P M35R R15I R15S S10N Y16C A39V Ala residues were mutated to Val D19A D24A E18A F21A G20A I28A I32A I33A K13A L42A M35A N12A N31A P30A R14A R15A Y16A Y27A I5A K6A P38A Q17A S10A Arg14 Arg15 K13R Lys13 R14K R15K

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the L23F and N31A mutations alter the molecular function of PTEN, specifically its PIP3 catalytic activity and nuclear accumulation, indicating changes in biochemical function. Oncogenic: The results indicate that the L23F mutation leads to a complete loss-of-function in terms of cell growth inhibitory capacity, suggesting that it contributes to tumor development or progression.

Gene→Variant (gene-first): 5728:L23F 5728:N31A

Genes: 5728

Variants: L23F N31A

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific mutations (K13R, R14K, K13E, etc.) affect the molecular functions of PTEN, including its nuclear localization and phosphatase activity, indicating alterations in biochemical function. Oncogenic: The mutations are described in the context of their role in PTEN's function related to tumor development, particularly in terms of phosphatase activity and localization, which are critical for its tumor suppressor role.

Gene→Variant (gene-first): 100329167:Arg14 5728:Arg15 5728:K13A 5728:K13E 5728:K13R 5728:Lys13 100329167:R14A 100329167:R14K 5728:R15A 5728:R15K

Genes: 100329167 5728

Variants: Arg14 Arg15 K13A K13E K13R Lys13 R14A R14K R15A R15K

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific mutations alter PTEN's phosphatase activity and nuclear accumulation, indicating that these variants affect molecular function. Oncogenic: The context implies that the mutations contribute to the functional behavior of PTEN, which is known to be involved in tumor suppression, suggesting a role in tumor development or progression.

Gene→Variant (gene-first): 5728:A39V 5728:D24A 5728:I32A 5728:I33A 5728:I5A 5728:K6A 5728:L42A 5728:M35A 5728:P38A 5728:Q17A 5728:R15A 5728:S10A 5728:Y16A

Genes: 5728

Variants: A39V D24A I32A I33A I5A K6A L42A M35A P38A Q17A R15A S10A Y16A

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Justification: Functional: The passage discusses how specific mutations in the PTEN N-terminal region alter its subcellular localization, indicating that these variants affect the molecular function of the protein.

Gene→Variant (gene-first): 5728:A39V 5728:Ala residues were mutated to Val 71:D19A 5728:D24A 5728:E18A 5728:F21A 5728:G20A 5728:I28A 5728:I32A 5728:I33A 5728:K13A 5728:L42A 5728:M35A 5728:N12A 5728:N31A 5728:P30A 100329167:R14A 5728:R15A 5728:Y16A 5728:Y27A

Genes: 5728 71 100329167

Variants: A39V Ala residues were mutated to Val D19A D24A E18A F21A G20A I28A I32A I33A K13A L42A M35A N12A N31A P30A R14A R15A Y16A Y27A

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the mutations alter the PIP3 phosphatase activity of PTEN, indicating that these variants affect molecular function. Oncogenic: The variants are described as "tumor-associated" and their effects on PTEN activity suggest a contribution to tumor development or progression.

Gene→Variant (gene-first): 5728:A34D 5728:A34V 5728:D24Y 5728:G36R 5728:I33S 5728:K13E 5728:L23F 5728:L42P 5728:M35R 5728:R15I 5728:R15S 5728:S10N 5728:Y16C

Genes: 5728

Variants: A34D A34V D24Y G36R I33S K13E L23F L42P M35R R15I R15S S10N Y16C

[Paragraph-level] PMCID: PMC4398541 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Justification: Functional: The passage discusses how various PTEN mutations alter the nuclear/cytosolic localization and function of the protein, indicating changes in molecular or biochemical function.

Gene→Variant (gene-first): 5728:A34D 5728:A34V 5728:D24Y 5728:G36R 5728:I33S 5728:K13E 5728:L23F 5728:L42P 5728:M35R 5728:R15I 5728:R15S 5728:S10N 5728:Y16C

Genes: 5728

Variants: A34D A34V D24Y G36R I33S K13E L23F L42P M35R R15I R15S S10N Y16C

[Paper-level Aggregated] PMCID: PMC4385014

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The L858R and T790M mutations in the EGFR gene are associated with altered sensitivity to erlotinib, indicating their role in promoting cancer cell proliferation and resistance to treatment. Predictive: The presence of the L858R and T790M mutations in NSCLC cell lines correlates with varying sensitivity to erlotinib, suggesting that these mutations can predict the response to this targeted therapy.

Gene→Variant (gene-first): EGFR(1956):L858R EGFR(1956):T790M

Genes: EGFR(1956)

Variants: L858R T790M

[Paper-level Aggregated] PMCID: PMC4378307

Evidence Type(s): Prognostic, Oncogenic

Justification: Prognostic: The text indicates that KRAS mutations, specifically G12D and G12S, are associated with poor prognosis in progression-free survival (PFS), demonstrating their role as independent negative prognostic factors. Oncogenic: The presence of KRAS mutations, including G12D and G12S, is indicative of oncogenic activity, as they are associated with worse clinical outcomes in patients.

Gene→Variant (gene-first): KRAS(3845):G12D KRAS(3845):G12S

Genes: KRAS(3845)

Variants: G12D G12S

[Paper-level Aggregated] PMCID: PMC4320693

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The passage indicates that specific mutations, particularly p.His1047Arg and p.His1047Leu, are associated with distinct phenotypes in a significant proportion of patients, suggesting their role in tumorigenesis. Prognostic: The correlation of specific mutations with phenotypes such as FAO, HHML, and CLOVES syndrome implies that these mutations may provide prognostic information regarding disease manifestation and patient outcomes.

Gene→Variant (gene-first): PIK3CA(5290):C420R PIK3CA(5290):E542K PIK3CA(5290):E545K PIK3CA(5290):H1047L PIK3CA(5290):H1047R PIK3CA(5290):p.Cys420Arg PIK3CA(5290):p.Glu542Lys PIK3CA(5290):p.Glu545Lys PIK3CA(5290):p.His1047Arg PIK3CA(5290):p.His1047Leu

Genes: PIK3CA(5290)

Variants: C420R E542K E545K H1047L H1047R p.Cys420Arg p.Glu542Lys p.Glu545Lys p.His1047Arg p.His1047Leu

[Paragraph-level] PMCID: PMC4320693 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the correlation of specific genotypes with phenotypes, indicating that the variants are associated with defining or classifying certain conditions such as FAO, HHML, or CLOVES syndrome. Oncogenic: The variants mentioned are associated with specific phenotypes that suggest a role in tumor development or progression, particularly in the context of CLOVES syndrome and other related conditions.

Gene→Variant (gene-first): 5290:p.Cys420Arg 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.His1047Arg 5290:p.His1047Leu

Genes: 5290

Variants: p.Cys420Arg p.Glu542Lys p.Glu545Lys p.His1047Arg p.His1047Leu

[Paragraph-level] PMCID: PMC4320693 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the frequency of specific mutations in patients, indicating their association with a disease or subtype. Oncogenic: The variants mentioned are likely somatic mutations that contribute to tumor development, as they are described in the context of patient mutations.

Gene→Variant (gene-first): 5290:C420R 5290:E542K 5290:E545K 5290:H1047L 5290:H1047R 5290:p.Cys420Arg 5290:p.Glu542Lys 5290:p.Glu545Lys 5290:p.His1047Arg 5290:p.His1047Leu

Genes: 5290

Variants: C420R E542K E545K H1047L H1047R p.Cys420Arg p.Glu542Lys p.Glu545Lys p.His1047Arg p.His1047Leu

[Paper-level Aggregated] PMCID: PMC4239128

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of the BRAF p.V600E mutation is associated with the malignancy's potential vulnerability to targeted therapy, indicating its role in driving cancer progression. Predictive: The high allele frequency of the BRAF p.V600E mutation suggests that the malignancy may respond to BRAF inhibition, which was confirmed by the patient's positive response to treatment with dabrafenib and trametinib. Prognostic: The use of dual BRAF and MEK inhibition was intended to prolong survival and optimize quality of life, indicating that the presence of the BRAF mutation has implications for the patient's prognosis.

Gene→Variant (gene-first): BRAF(673):1799T > A BRAF(673):p.V600E BRAF(673):V600E

Genes: BRAF(673)

Variants: 1799T > A p.V600E V600E

[Paragraph-level] PMCID: PMC4239128 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the patient's excellent response to dual therapy with dabrafenib and trametinib, indicating that the BRAF V600E mutation correlates with treatment response. Oncogenic: The BRAF V600E variant is described in the context of a poorly differentiated intrahepatic cholangiocarcinoma, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E

[Paper-level Aggregated] PMCID: PMC4234187

Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

Justification: Oncogenic: The introduction of the C118S mutation into the Kras gene was shown to affect tumorigenesis, specifically leading to fewer lung tumors in Kras+/C118S and KrasC118S/C118S mice when treated with the carcinogen urethane, indicating a role in oncogenic processes. Functional: The study demonstrated that the C118S mutation alters the function of the Kras protein, as it specifically blocks redox-dependent reactions that lead to Ras activation, impacting downstream signaling pathways such as the MAPK pathway. Predictive: The presence of the C118S mutation was associated with a reduced tumor burden and a shift towards smaller tumors in mice, suggesting that this mutation can predict a lower likelihood of tumor development in response to carcinogenic exposure. Prognostic: The findings indicate that mice with the C118S mutation have a different tumorigenic outcome compared to those with wild-type Kras, which could be used to prognosticate the progression and severity of lung tumors in a carcinogen-induced model.

Gene→Variant (gene-first): NOS2(4843):C118 NOS2(4843):C118S KRAS(3845):G13D NRAS(4893):Q61L NOS2(4843):G353 transversion to C NOS2(4843):G353>C NOS2(4843):cysteine 118 KRAS(3845):G12D NOS3(4846):S1177D KRAS(3845):Q61R/L NRAS(4893):Q61R

Genes: NOS2(4843) KRAS(3845) NRAS(4893) NOS3(4846)

Variants: C118 C118S G13D Q61L G353 transversion to C G353>C cysteine 118 G12D S1177D Q61R/L Q61R

[Paragraph-level] PMCID: PMC4234187 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the introduction of a C118S mutation into the Kras allele and its effect on tumorigenesis, indicating that this somatic variant contributes to tumor development or progression. Functional: The passage describes how the thiol residue of cysteine 118 is involved in redox-dependent reactions that lead to Ras activation, suggesting that the C118S mutation alters molecular function related to protein activity.

Gene→Variant (gene-first): 4843:C118 4843:C118S 4843:cysteine 118

Genes: 4843

Variants: C118 C118S cysteine 118

[Paper-level Aggregated] PMCID: PMC4159563

Evidence Type(s): Prognostic, Oncogenic, Predictive

Justification: Prognostic: The presence of the K27M mutation in histone H3 is associated with worse overall survival in DIPG patients, as indicated by the significant difference in survival rates between patients with K27M mutations and those without. Oncogenic: The K27M-H3 mutation is found exclusively in high-grade astrocytomas and is associated with aggressive clinical behavior, suggesting its role in tumorigenesis. Predictive: The study indicates that histone mutation status, particularly K27M, is a significant predictor of overall survival, which may inform treatment decisions for DIPG patients.

Gene→Variant (gene-first): ACVR1(90):K27M PIK3CA(5290):p.Glu545Gly ACVR1(90):p.Gly328Val

Genes: ACVR1(90) PIK3CA(5290)

Variants: K27M p.Glu545Gly p.Gly328Val

[Paper-level Aggregated] PMCID: PMC4150988

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The text indicates that RIT1 mutations, particularly in the switch II domain, are associated with the ability to induce cellular transformation and tumor formation, suggesting their role as oncogenes in lung adenocarcinoma. Functional: The study demonstrates that mutated RIT1 can activate signaling pathways (MEK/ERK and PI3K/AKT) and induce cellular transformation, indicating a functional impact of these mutations on cellular behavior. Predictive: The presence of RIT1 mutations, particularly in the context of lung adenocarcinoma, may predict the activation of specific signaling pathways and the potential for tumor formation, as evidenced by the transformation assays conducted in the study.

Gene→Variant (gene-first): RIT1(6016):F82L RIT1(6016):M90I RIT1(6016):p.M90I KRAS(3845):G12V EGFR(1956):L858R RIT1(6016):Q40 RIT1(6016):Q40L RIT1(6016):Q79L NA:alanine 77 RIT1(6016):p.A77P RIT1(6016):p.A77S RIT1(6016):p.R122L

Genes: RIT1(6016) KRAS(3845) EGFR(1956) NA

Variants: F82L M90I p.M90I G12V L858R Q40 Q40L Q79L alanine 77 p.A77P p.A77S p.R122L

[Paper-level Aggregated] PMCID: PMC3997489

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The text indicates that nearly 80% of DIPGs harbor a K27M mutation, suggesting that this variant is associated with the disease and contributes to its oncogenic properties. Prognostic: The identification of distinct molecular subgroups, including those with the K27M mutation, implies that this variant may have implications for disease progression and patient outcomes in DIPG.

Gene→Variant (gene-first): H3-3B(3021):K27M

Genes: H3-3B(3021)

Variants: K27M

[Paragraph-level] PMCID: PMC3997489 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the prevalence of the K27M mutation in DIPG, indicating its association with this specific disease, which supports its use as a biomarker for classification. Oncogenic: The K27M mutation is described as part of the unique genetic make-up of DIPG, suggesting its contribution to tumor development or progression in this specific cancer type.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

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thats HARD (hitting) - discussed in class - Nick: new-ish concept

[Paper-level Aggregated] PMCID: PMC3973211

Evidence Type(s): Prognostic, Oncogenic, Functional

Justification: Prognostic: The text indicates that mutations on Arg248 and Arg282 residues are associated with significantly shorter overall survival times in cancer patients, as demonstrated by Kaplan-Meier survival analysis and multivariate Cox regression analysis. Oncogenic: The passage discusses how p53 mutations, particularly R248 and R282, confer novel oncogenic functions and are linked to increased expression of drug metabolism enzymes, suggesting a role in cancer progression and treatment resistance. Functional: The evidence shows that p53 mutations R248W and R282W induce higher expression of the CYP3A4 enzyme, which is involved in drug metabolism, indicating a functional impact of these mutations on cellular processes related to chemotherapy response.

Gene→Variant (gene-first): TP53(7157):Arg248 TP53(7157):Arg282 TP53(7157):G245 TP53(7157):R175 TP53(7157):R248 TP53(7157):R249S TP53(7157):R273 TP53(7157):R282 TP53(7157):Y220 TP53(7157):R282W TP53(7157):R175H TP53(7157):R248W TP53(7157):R273H TP53(7157):R248Q/W

Genes: TP53(7157)

Variants: Arg248 Arg282 G245 R175 R248 R249S R273 R282 Y220 R282W R175H R248W R273H R248Q/W

[Paragraph-level] PMCID: PMC3973211 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Prognostic, Predictive, Oncogenic

Justification: Prognostic: The passage indicates that mutations at Arg248 and Arg282 positions are associated with shorter patient survival, suggesting a correlation with disease outcome independent of therapy. Predictive: The passage discusses the association of p53 mutations with resistance to several CYP3A4-metabolized chemotherapeutic drugs, indicating a correlation with treatment response. Oncogenic: The mention of p53 mutations contributing to gain of novel oncogenic functions and their association with cancer cell lines suggests that these somatic variants play a role in tumor development or progression.

Gene→Variant (gene-first): 7157:Arg248 7157:Arg282 7157:R282W

Genes: 7157

Variants: Arg248 Arg282 R282W

[Paper-level Aggregated] PMCID: PMC3923676

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The E384X mutation in ERRFI1 is described as a loss of function mutation that leads to nearly complete loss of function, suggesting its role in tumorigenesis by negatively regulating EGFR activation. Predictive: The presence of the E384X mutation in ERRFI1 was associated with rapid and robust disease regression when treated with erlotinib, indicating its potential as a predictive biomarker for response to EGFR inhibitors.

Gene→Variant (gene-first): BRCA1(672):E384X

Genes: BRCA1(672)

Variants: E384X

[Paper-level Aggregated] PMCID: PMC3727232

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of BRAF:p.V600E mutations and H3F3A:p.K27M mutations in various tumor types suggests that these variants are associated with oncogenesis, as they recur in specific histopathological subtypes and are linked to tumor development. Predictive: The identification of BRAF:p.V600E mutations in a high proportion of pleomorphic xanthoastrocytomas indicates that this variant may predict response to targeted therapies that inhibit the BRAF pathway. Prognostic: The frequency of BRAF:p.V600E mutations in different tumor types, particularly in pleomorphic xanthoastrocytomas, may provide prognostic information regarding tumor behavior and patient outcomes.

Gene→Variant (gene-first): H3-3B(3021):p.K27M BRAF(673):p.V600E

Genes: H3-3B(3021) BRAF(673)

Variants: p.K27M p.V600E

[Paper-level Aggregated] PMCID: PMC3542862

Evidence Type(s): Oncogenic, Functional, Predisposing

Justification: Oncogenic: The mutations in PIK3CA, including R115P, E542K, and H1047L/R, are described as gain-of-function mutations that activate the PI3K/AKT signaling pathway, which is known to be involved in cancer development. Functional: The presence of mutations such as R115P and E542K in PIK3CA leads to increased AKT activation, indicating a functional consequence of these mutations in the signaling pathway. Predisposing: The identification of somatic mutations in PIK3CA associated with macrodactyly suggests a genetic predisposition to this condition, as these mutations are linked to the activation of pathways involved in growth and development.

Gene→Variant (gene-first): UBXN11(91544):C392G PDK1(5163):R115P PIK3CA(5290):E542K PIK3CA(5290):H1047L PIK3CA(5290):H1047R PIK3CA(5290):p.Glu542 PIK3CA(5290):p.His1047 PIK3CA(5290):R115L PIK3CA(5290):p.Arg115

Genes: UBXN11(91544) PDK1(5163) PIK3CA(5290)

Variants: C392G R115P E542K H1047L H1047R p.Glu542 p.His1047 R115L p.Arg115

[Paper-level Aggregated] PMCID: PMC3483540

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The text identifies several mutations (e.g., L858R, G719A, G12C, G12V, G12D, G12S, G13C, G13D, Q61H, Q61L, Q61K, H1047R, E555K, V600E, D32G, M1124D) as driver mutations in lung adenocarcinoma, indicating their role in cancer development. Predictive: The presence of specific driver mutations in genes such as EGFR and KRAS suggests potential predictive value for targeted therapies in lung adenocarcinoma, as these mutations are known to influence treatment responses. Prognostic: The text discusses the correlation between the number of mutations and smoking status, which may have implications for prognosis in lung cancer patients, indicating that a higher mutation burden could be associated with disease outcomes.

Gene→Variant (gene-first): FBLN2(2199):C > A FBLN2(2199):T > G CTNNB1(1499):D32G LMTK2(22853):E555K KRAS(3845):G12C KRAS(3845):G12D KRAS(3845):G12S KRAS(3845):G12V KRAS(3845):G13C KRAS(3845):G13D EGFR(1956):G719A PIK3CA(5290):H1047R EGFR(1956):L858R CTNNB1(1499):M1124D KRAS(3845):Q61H NRAS(4893):Q61K NRAS(4893):Q61L BRAF(673):V600E

Genes: FBLN2(2199) CTNNB1(1499) LMTK2(22853) KRAS(3845) EGFR(1956) PIK3CA(5290) NRAS(4893) BRAF(673)

Variants: C > A T > G D32G E555K G12C G12D G12S G12V G13C G13D G719A H1047R L858R M1124D Q61H Q61K Q61L V600E

[Paragraph-level] PMCID: PMC3483540 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage discusses the presence of somatic point mutations, specifically the C > A and T > G transversions, in lung cancers of smokers, indicating their contribution to tumor development or progression. Diagnostic: The differences in mutational spectrums between lung cancers of smokers and never-smokers suggest that these variants can be used to classify or define the disease based on smoking status.

Gene→Variant (gene-first): 2199:C > A 2199:T > G

Genes: 2199

Variants: C > A T > G

[Paragraph-level] PMCID: PMC3483540 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage discusses several somatic mutations, including those in EGFR, KRAS, NRAS, PIK3CA, BRAF, CTNNB1, and MET, which are identified as driver mutations contributing to lung adenocarcinoma, indicating their role in tumor development or progression. Diagnostic: The passage mentions that specific mutations in well-known cancer genes are associated with lung adenocarcinoma, suggesting that these variants can be used to classify or define the disease.

Gene→Variant (gene-first): 1499:D32G 22853:E555K 3845:G12C 3845:G12D 3845:G12S 3845:G12V 3845:G13C 3845:G13D 1956:G719A 5290:H1047R 1956:L858R 1499:M1124D 3845:Q61H 4893:Q61K 4893:Q61L 673:V600E

Genes: 1499 22853 3845 1956 5290 4893 673

Variants: D32G E555K G12C G12D G12S G12V G13C G13D G719A H1047R L858R M1124D Q61H Q61K Q61L V600E

[Paper-level Aggregated] PMCID: PMC3461408

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The text identifies the cancer-associated mutations p.His1047Leu and p.His1047Arg in PIK3CA, which are linked to a syndrome characterized by overgrowth, indicating their role in tumorigenesis. Functional: The evidence shows that affected dermal fibroblasts exhibit enhanced phosphatidylinositol-3,4,5-trisphosphate generation and activation of downstream signaling, demonstrating the functional impact of the mutations on PI3K signaling.

Gene→Variant (gene-first): PIK3CA(5290):p.His1047Arg PIK3CA(5290):p.His1047Leu

Genes: PIK3CA(5290)

Variants: p.His1047Arg p.His1047Leu

[Paragraph-level] PMCID: PMC3461408 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the identification of cancer-associated mutations p.His1047Leu and p.His1047Arg in PIK3CA, which are linked to a syndrome characterized by overgrowth, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage describes how affected dermal fibroblasts showed enhanced phosphatidylinositol-3,4,5-trisphosphate (PIP3) generation and activation of downstream signaling, demonstrating that the variants alter molecular or biochemical function.

Gene→Variant (gene-first): 5290:p.His1047Arg 5290:p.His1047Leu

Genes: 5290

Variants: p.His1047Arg p.His1047Leu

[Paper-level Aggregated] PMCID: PMC3422615

Evidence Type(s): Prognostic, Oncogenic, Predictive

Justification: Prognostic: The K27M-H3.3 mutation is associated with significantly worse overall survival in DIPG patients, with a mean survival of 0.73 years compared to 4.59 years for wild-type patients, indicating its role as a prognostic marker. Oncogenic: The K27M-H3.3 mutation is prevalent in DIPGs and is associated with specific copy number alterations and distinct clinical outcomes, suggesting its role in tumorigenesis. Predictive: The findings advocate for H3.3-mutation testing at diagnosis to inform therapeutic trial design and clinical decision-making, indicating its potential to predict treatment response.

Gene→Variant (gene-first): H3-3B(3021):G34V/R H3-3B(3021):K27M H3-3B(3021):G34V

Genes: H3-3B(3021)

Variants: G34V/R K27M G34V

[Paragraph-level] PMCID: PMC3422615 Section: RESULTS PassageIndex: 12

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses the correlation between the K27M-H3.3 mutation and overall survival in DIPG patients, indicating that patients with this mutation have significantly worse survival outcomes compared to those with wild-type tumors. Diagnostic: The K27M-H3.3 mutation is associated with the classification of DIPG patients, as it is mentioned that 69% of the patients carried this mutation, which is relevant for defining their disease status.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC3422615 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage discusses frequent focal copy number alterations in the K27M-H3.3 group, indicating that the K27M variant is associated with tumor development through specific genetic alterations. Diagnostic: The mention of the K27M-H3.3 group suggests that the K27M variant is used to classify or define a specific subtype of tumors, indicating its role in disease classification.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC3422615 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the K27M-H3.3 mutation in the context of DNA copy number alterations in tumors, indicating its role in tumor development or progression through the identification of specific chromosomal changes associated with this variant.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC3422615 Section: RESULTS PassageIndex: 7

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of the K27M variant in DIPG samples and its association with TP53 mutations, indicating its role in classifying or defining a subtype of disease. Oncogenic: The K27M variant is mentioned in the context of mutations found in DIPG samples, suggesting its contribution to tumor development or progression in this specific cancer type.

Gene→Variant (gene-first): 3021:K27M

Genes: 3021

Variants: K27M

[Paragraph-level] PMCID: PMC3422615 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the association of the K27M-H3.3 mutation with ATRX mutations in DIPG samples, indicating its role in defining or classifying a subtype of disease. Oncogenic: The K27M-H3.3 mutation is mentioned in the context of its presence in GBM samples, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 3021:G34V/R 3021:K27M

Genes: 3021

Variants: G34V/R K27M

[Paragraph-level] PMCID: PMC3422615 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The K27M mutation is identified as being present at diagnosis in DIPG samples, indicating its role in defining the disease subtype. Oncogenic: The K27M mutation contributes to tumor development in DIPG, as it is recurrently found in the samples analyzed, suggesting its role in tumor progression.

Gene→Variant (gene-first): 3021:G34V/R 3021:K27M

Genes: 3021

Variants: G34V/R K27M

[Paper-level Aggregated] PMCID: PMC3383766

Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

Justification: Oncogenic: The text describes multiple mutations in genes associated with cancer, including those in druggable tyrosine kinase domains, indicating their potential role in oncogenesis. Functional: The identification of mutations leading to functional inactivation of MAP3K1 and MAP2K4 suggests that these mutations affect the normal function of these genes, which are involved in critical signaling pathways. Predictive: The mention of mutations in druggable tyrosine kinase domains implies that these mutations may predict response to targeted therapies, as they are associated with specific cancer treatments. Prognostic: The correlation of mutation frequencies with clinical outcomes, such as the association of CDH1 mutations with lobular breast cancer, suggests that these mutations may have prognostic implications.

Gene→Variant (gene-first): DDR1(780):A829V AKT1(207):C77F ARNT(405):D735H NRG1(3084):E583D EPHB2(2048):E924K PDGFRA(5156):M875L DDR1(780):R611C AKT2(208):S11F FOXA1(3169):S375F ERBB2(2064):V777L KMT2B(9757):G168E SF3B1(23451):K666Q SF3B1(23451):K700E MAP3K4(4216):N104S RUNX1(861):R166Q CYP19A1(1588):R169K ARID4B(51742):S184L GATA3(2625):M294K AGTR2(186):R251H AGTR2(186):V184I

Genes: DDR1(780) AKT1(207) ARNT(405) NRG1(3084) EPHB2(2048) PDGFRA(5156) AKT2(208) FOXA1(3169) ERBB2(2064) KMT2B(9757) SF3B1(23451) MAP3K4(4216) RUNX1(861) CYP19A1(1588) ARID4B(51742) GATA3(2625) AGTR2(186)

Variants: A829V C77F D735H E583D E924K M875L R611C S11F S375F V777L G168E K666Q K700E N104S R166Q R169K S184L M294K R251H V184I

[Paper-level Aggregated] PMCID: PMC3378484

Evidence Type(s): Oncogenic, Functional, Predictive, Prognostic

Justification: Oncogenic: The text discusses somatic mutations in PIK3CA, including several specific variants (e.g., E545K, H1047R, C420R) that are characterized as activating mutations associated with increased lipid kinase activity, which is a hallmark of oncogenic mutations in cancer. Functional: The evidence indicates that specific mutations (e.g., C420R, E545K, H1047R) enhance lipid binding and kinase activity, demonstrating a functional impact on the protein's activity and its role in signaling pathways. Predictive: The text suggests that the presence of certain mutations correlates with enhanced lipid binding and kinase activity, which could be used to predict the functional outcomes of these mutations in cancer contexts. Prognostic: The correlation between specific mutations and increased lipid kinase activity implies that these mutations could serve as prognostic markers for cancer progression and response to therapies targeting the PI3K pathway.

Gene→Variant (gene-first): PIK3CA(5290):C420 PIK3CA(5290):C420R PIK3CA(5290):E545K PIK3R1(5295):N345 PIK3R1(5295):N564 PIK3R1(5295):N564D PIK3CA(5290):G1049R PIK3CA(5290):H1047L PIK3CA(5290):H1047R PIK3CA(5290):M1043I PIK3CA(5290):D915N PIK3CA(5290):H1047 PIK3CG(5294):K942 PIK3CG(5294):R949 PIK3CG(5294):K942Q PIK3CG(5294):R949D PIK3CA(5290):deletion of residues 1051-1068

Genes: PIK3CA(5290) PIK3R1(5295) PIK3CG(5294)

Variants: C420 C420R E545K N345 N564 N564D G1049R H1047L H1047R M1043I D915N H1047 K942 R949 K942Q R949D deletion of residues 1051-1068

[Paper-level Aggregated] PMCID: PMC3366948

Evidence Type(s): Oncogenic, Functional, Predisposing, Diagnostic, Prognostic

Justification: Oncogenic: The text states that JAK2 and JAK3 are known oncogenes in leukemia, and specific mutations such as M511I and A572V have been shown to induce leukemia in mice, indicating their oncogenic potential. Functional: The M511I mutation was shown to transform IL3 dependent 32D cells and induce T-ALL in mice, demonstrating a functional impact on cellular behavior. Predisposing: The presence of mutations in JAK2 and JAK3 in T-ALL patients suggests a predisposition to developing this type of leukemia, as these mutations were identified in patient samples. Diagnostic: The identification of specific mutations in JAK2 and JAK3 in T-ALL patients can serve as diagnostic markers for the disease, as indicated by their presence in patient samples. Prognostic: The somatic status of the H1297Y variant in TET1, confirmed in a remission sample, suggests that it may have implications for prognosis in T-ALL patients.

Gene→Variant (gene-first): MST1R(4486):A35V PMS2(5395):C192Y TYK2(7297):R1027H JAK3(3718):A572 JAK3(3718):A572T JAK3(3718):A572V JAK3(3718):M511I TET1(80312):H1297Y

Genes: MST1R(4486) PMS2(5395) TYK2(7297) JAK3(3718) TET1(80312)

Variants: A35V C192Y R1027H A572 A572T A572V M511I H1297Y

[Paper-level Aggregated] PMCID: PMC3293822

Evidence Type(s): Oncogenic, Functional, Predisposing

Justification: Oncogenic: The text discusses multiple mutations in the androgen receptor (AR) that are associated with prostate cancer (PCa), indicating that these mutations can drive cancer progression through altered transactivational activity and interaction with co-regulators. Functional: The evidence describes various mutations that exhibit changes in transactivational activity, including loss of function and gain of function, demonstrating their impact on AR function and signaling pathways relevant to prostate cancer. Predisposing: The mention of mutations such as K720E and R726L being implicated in a 6-fold increased risk of prostate cancer suggests a predisposition to developing the disease due to these genetic alterations.

Gene→Variant (gene-first): CREBBP(1387):A234 AKT1(207):D221 AR(367):D528 AR(367):E198 FDXR(2232):G142 AR(367):G166 AR(367):G524 AR(367):L57 AR(367):M523 AR(367):M537 AR(367):P269 FDXR(2232):P340 AR(367):P390 AR(367):P514 MYBBP1A(10514):P515 AR(367):P533 AR(367):S296 AR(367):S334 CREBBP(1387):A234T AKT1(207):D221H AR(367):D528G AR(367):E198G AR(367):L57Q FDXR(2232):P340L NCOR1(9611):P504L AR(367):S296R AR(367):S334P BCL2A1(597):A586V AR(367):A587S NR3C1(2908):I672T NCOA2(10499):R629Q NCOA2(10499):T575A AR(367):A748V AR(367):A765T NCOR1(9611):K720E AR(367):L744F CREBBP(1387):M749 CREBBP(1387):M749I NCOR1(9611):M886V AR(367):N756D MYBBP1A(10514):Q798E AR(367):Q902R AR(367):R726L AR(367):S759P MYBBP1A(10514):V757A MYBBP1A(10514):V757I AR(367):Y763C AR(367):N756 AR(367):Q902 NCOR1(9611):lysine 720 AR(367):P269S NCOA2(10499):D879G AR(367):H874Y AR(367):Q919R AR(367):T877A FDXR(2232):G142V AR(367):G524D AR(367):M523V AR(367):M537V AR(367):P533S AR(367):P390L AR(367):G166S AR(367):M537R NR3C1(2908):I672 NCOA2(10499):R629 NCOA2(10499):T575 AR(367):K910R NCOR1(9611):M886 NCOR1(9611):M886I AR(367):P514S MYBBP1A(10514):S515G

Genes: CREBBP(1387) AKT1(207) AR(367) FDXR(2232) MYBBP1A(10514) NCOR1(9611) BCL2A1(597) NR3C1(2908) NCOA2(10499)

Variants: A234 D221 D528 E198 G142 G166 G524 L57 M523 M537 P269 P340 P390 P514 P515 P533 S296 S334 A234T D221H D528G E198G L57Q P340L P504L S296R S334P A586V A587S I672T R629Q T575A A748V A765T K720E L744F M749 M749I M886V N756D Q798E Q902R R726L S759P V757A V757I Y763C N756 Q902 lysine 720 P269S D879G H874Y Q919R T877A G142V G524D M523V M537V P533S P390L G166S M537R I672 R629 T575 K910R M886 M886I P514S S515G

[Paper-level Aggregated] PMCID: PMC3288377

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The text indicates that the p.K27M mutation is present in a significant percentage of DIPGs, suggesting its role in tumorigenesis. Additionally, the presence of p.G34R mutations in non-BS-PGs further supports their potential oncogenic nature. Predictive: The identification of specific mutations such as p.K27M and p.G34R in DIPGs and non-BS-PGs may help predict the behavior of these tumors and their response to targeted therapies.

Gene→Variant (gene-first): H3-3B(3021):p.G34R H3-3B(3021):p.K27M

Genes: H3-3B(3021)

Variants: p.G34R p.K27M

[Paper-level Aggregated] PMCID: PMC3287118

Evidence Type(s): nan

Justification: No positive paragraphs to aggregate.

Gene→Variant (gene-first):

Genes:

Variants:

[Paper-level Aggregated] PMCID: PMC3266695

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text discusses the presence of the BRAF(V600E) mutation in melanomas and its role in promoting tumor growth, indicating its oncogenic potential. Predictive: The evidence suggests that the presence of BRAF(V600E) is predictive of response to RAF inhibitors, as these drugs have remarkable clinical activity in patients with this specific mutation. Functional: The text describes the functional consequences of the BRAF(V600E) mutation, including its role in dimerization and resistance to RAF inhibitors, demonstrating its functional impact on ERK signaling.

Gene→Variant (gene-first): BRAF(673):V600E

Genes: BRAF(673)

Variants: V600E

[Paragraph-level] PMCID: PMC3266695 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the presence of the BRAF(V600E) variant correlates with the clinical activity of RAF inhibitors in melanoma patients, indicating a relationship between the variant and treatment response. Oncogenic: The BRAF(V600E) variant is described as contributing to tumor development and progression, particularly in the context of its role in ERK signaling and the development of resistance mechanisms in melanoma.

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E

[Paper-level Aggregated] PMCID: PMC3260002

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of DNMT3A exon 23 mutations, particularly at the R882 codon, is associated with acute myeloid leukemia (AML), indicating a role in tumorigenesis. Predictive: The identification of specific mutations in DNMT3A may help predict the response to certain treatments in AML patients, as these mutations are known to influence disease characteristics. Prognostic: The detection of DNMT3A mutations, especially at the R882 codon, can provide information about the likely course and outcome of the disease in AML patients.

Gene→Variant (gene-first): DNMT3A(1788):R882 DNMT3A(1788):R882C DNMT3A(1788):R882H DNMT3A(1788):R882P DNMT3A(1788):W893 DNMT3A(1788):W893S

Genes: DNMT3A(1788)

Variants: R882 R882C R882H R882P W893 W893S

[Paper-level Aggregated] PMCID: PMC3244026

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The text describes how ETV6 mutations (Y103fs, S105fs, V345fs, N356fs) result in functionally inactive proteins that lack transcriptional repression activity, indicating their functional consequences in the context of leukemia. Oncogenic: The presence of ETV6 mutations is associated with a characteristic gene expression signature in immature adult T cell leukemias, suggesting a role in leukemia development and indicating their oncogenic potential.

Gene→Variant (gene-first): ETV6(2120):N356fs ETV6(2120):S105fs ETV6(2120):V345fs ETV6(2120):Y103fs

Genes: ETV6(2120)

Variants: N356fs S105fs V345fs Y103fs

[Paper-level Aggregated] PMCID: PMC3219854

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The missense point mutation Trp557Gly in KIT exon 11 was identified in the tumor, indicating a potential role in tumorigenesis, particularly in the context of neurofibromatosis type 1-associated GISTs. Functional: The identification of the Trp557Gly mutation suggests a functional alteration in the KIT protein that may contribute to the development of the tumors, as it is associated with the pathogenesis of GISTs.

Gene→Variant (gene-first): KIT(3815):Trp557Gly

Genes: KIT(3815)

Variants: Trp557Gly

[Paper-level Aggregated] PMCID: PMC3184204

Evidence Type(s): Predisposing, Diagnostic, Prognostic, Functional

Justification: Predisposing: The text indicates that the c.1061C>T and c.1063_1065delACA mutations in the GATA2 gene are associated with multigenerational transmission of myelodysplastic syndrome (MDS) and acute myeloid leukemia (AML), suggesting a predisposition to these conditions. Diagnostic: The identification of GATA2 mutations as predisposing factors for MDS/AML can aid in the diagnosis of these conditions in affected families. Prognostic: The mention of these mutations being critical for effective prognosis indicates that they may provide information about the likely course or outcome of MDS/AML in affected individuals. Functional: The text discusses the differential effects of the mutations on transactivation of target genes, cellular differentiation, apoptosis, and global gene expression, indicating functional consequences of the variants.

Gene→Variant (gene-first): GATA2(2624):c.1061C>T GATA2(2624):c.1063_1065delACA GATA2(2624):p.Thr354Met SPI1(6688):p.Thr355del

Genes: GATA2(2624) SPI1(6688)

Variants: c.1061C>T c.1063_1065delACA p.Thr354Met p.Thr355del

[Paper-level Aggregated] PMCID: PMC3141770

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The presence of PIK3CA mutations, specifically H1047R and E542K, is associated with tumorigenesis, as indicated by their occurrence in tumor samples and the context of their mutation hotspots. Prognostic: The study suggests a correlation between PIK3CA mutations and PTEN expression loss, which may have implications for patient outcomes, particularly since a significant portion of patients with the H1047R mutation also exhibited PTEN loss.

Gene→Variant (gene-first): PIK3CA(5290):E542K PIK3CA(5290):H1047R PTEN(5728):T1052A

Genes: PIK3CA(5290) PTEN(5728)

Variants: E542K H1047R T1052A

[Paper-level Aggregated] PMCID: PMC3100313

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The presence of the IDH1 R132H mutation is associated with glioblastoma and is implicated in tumorigenesis through the alteration of normal enzyme function and the accumulation of oncometabolites like D-2-hydroxyglutarate. Predictive: The identification of the IDH1 R132H mutation in glioblastomas suggests that it may serve as a predictive biomarker for the presence of this specific mutation in tumor samples, which could influence treatment decisions. Functional: The mutation at codon 132 (R132H) results in a gain-of-function change that alters the enzymatic activity of IDH1, leading to the production of D-2-hydroxyglutarate, which is relevant to the functional consequences of the mutation in the context of glioblastoma.

Gene→Variant (gene-first): D2HGDH(728294):R132 L2HGDH(79944):arginine to histidine D2HGDH(728294):c.395G>A IDH1(3417):p.R132H IDH1(3417):R132H

Genes: D2HGDH(728294) L2HGDH(79944) IDH1(3417)

Variants: R132 arginine to histidine c.395G>A p.R132H R132H

[Paper-level Aggregated] PMCID: PMC3058384

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The B-RAFV600E mutation is described as an oncogenic mutation found in a significant percentage of malignant melanomas, indicating its role in cancer development. Predictive: The B-RAFV600E mutation predicts a dependency on the MAPK signaling cascade in melanoma, which is supported by the success of RAF and MEK inhibitors in clinical trials. Functional: The study functionally interrogates resistance mechanisms to a selective RAF kinase inhibitor in B-RAFV600E cell lines, identifying MAP3K8 as a factor driving resistance, demonstrating the functional implications of the variant.

Gene→Variant (gene-first): BRAF(673):B-RAFV600E BRAF(673):serine/threonine

Genes: BRAF(673)

Variants: B-RAFV600E serine/threonine

[Paper-level Aggregated] PMCID: PMC2970593

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The mutations identified in the EGFR tyrosine kinase domain, including L858R, are described as activating mutations that increase sensitivity to the EGFR inhibitor Erlotinib, indicating their role in promoting cancer progression. Predictive: The presence of the L858R mutation is associated with increased sensitivity to the EGFR inhibitor Erlotinib, suggesting its utility in predicting response to targeted therapy in patients with non-small cell lung cancer. Functional: The text states that all missense mutations, including the novel ones, were found to be activating mutations, indicating their functional impact on EGFR activity.

Gene→Variant (gene-first): EGFR(1956):C797 NA:E734 NA:T785 EGFR(1956):E868 EGFR(1956):L858 EGFR(1956):R831 NA:W731 EGFR(1956):Y801 EGFR(1956):C797Y EGFR(1956):E734Q EGFR(1956):E868G EGFR(1956):L831H EGFR(1956):L858R EGFR(1956):T785A EGFR(1956):W731L EGFR(1956):Y801H

Genes: EGFR(1956) NA

Variants: C797 E734 T785 E868 L858 R831 W731 Y801 C797Y E734Q E868G L831H L858R T785A W731L Y801H

[Paper-level Aggregated] PMCID: PMC2910708

Evidence Type(s): nan

Justification: No positive paragraphs to aggregate.

Gene→Variant (gene-first):

Genes:

Variants:

[Paragraph-level] PMCID: PMC2910708 Section: RESULTS PassageIndex: 16

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 3815:L588dup 3815:Y568del 3815:c.1661_1705del45bp 3815:c.1728_1766dup39bp 3815:c.1735_1737delGAT 3815:p.D579del

Genes: 3815

Variants: L588dup Y568del c.1661_1705del45bp c.1728_1766dup39bp c.1735_1737delGAT p.D579del

[Paragraph-level] PMCID: PMC2910708 Section: RESULTS PassageIndex: 5

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 5156:D842V

Genes: 5156

Variants: D842V

[Paragraph-level] PMCID: PMC2910708 Section: RESULTS PassageIndex: 4

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 5156:p.R822 H

Genes: 5156

Variants: p.R822 H

[Paper-level Aggregated] PMCID: PMC2848976

Evidence Type(s): Predictive, Oncogenic, Functional

Justification: Predictive: The study demonstrates that the presence of BRAF mutations, specifically BRAFV600E/K, predicts sensitivity to the drug PLX4032, as evidenced by the significantly lower IC50 values in BRAF mutant melanoma cell strains compared to BRAF wild-type cells. Oncogenic: The BRAFV600E/K mutations are described as frequent mutationally active tumor-specific kinases in melanomas, indicating their role in driving oncogenesis in these tumors. Functional: The study explores the functional effects of PLX4032 on ERK1/2 phosphorylation and downstream signaling pathways, demonstrating how BRAF mutations influence cellular responses to the drug.

Gene→Variant (gene-first): BRAF(673):BRAFV600E BRAF(673):BRAFV600K NRAS(4893):Q61L BRAF(673):V600E/K JUNB(3726):R89L BRAF(673):V600E

Genes: BRAF(673) NRAS(4893) JUNB(3726)

Variants: BRAFV600E BRAFV600K Q61L V600E/K R89L V600E

[Paragraph-level] PMCID: PMC2848976 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic, Functional

Justification: Predictive: The passage discusses how BRAFV600E/K is targeted for therapy with the specific inhibitor PLX4032, indicating a correlation with treatment response. Oncogenic: BRAFV600E/K is described as a mutationally active tumor-specific kinase in melanomas, suggesting its role in tumor development or progression. Functional: The passage mentions that PLX4032 alters the activity of ERK1/2 in BRAFV600E/K cells, indicating a change in molecular function related to the variant.

Gene→Variant (gene-first): 673:BRAFV600E 4893:Q61L 673:V600E/K

Genes: 673 4893

Variants: BRAFV600E Q61L V600E/K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 24

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how activated FAK has a functional impact on BRAFWT melanoma cells, specifically noting changes in colony formation and cell motility in response to PLX4032, indicating alterations in molecular or biochemical function. Oncogenic: The mention of BRAFWT and BRAFV600E in the context of melanoma cells suggests that these variants are involved in tumor behavior, particularly in how they respond to treatment and their migratory capabilities, indicating a role in tumor development or progression.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 23

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the effects of PLX4032 on melanoma cells, indicating a difference in response between BRAFWT and BRAFV600E cells, which suggests a correlation with treatment response. Oncogenic: The mention of BRAFV600E in the context of advanced melanoma cells implies that this somatic variant contributes to tumor development or progression, as it is associated with specific cellular behaviors in the study.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 21

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 4893:Q61L

Genes: 4893

Variants: Q61L

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 18

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of melanoma cells to the therapy PLX4032, indicating that the BRAFV600E variant is associated with a lack of activation of certain proteins in response to treatment, which suggests a predictive relationship regarding therapy response. Oncogenic: The mention of BRAFV600E in the context of melanoma cells implies its role as a somatic variant contributing to tumor development or progression, as it is a well-known oncogenic mutation in melanoma.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of BRAFV600E cells to PLX4032, indicating a correlation with treatment response. Oncogenic: The mention of BRAFV600E in the context of downregulation of FOS and the activation of ERK1/2 suggests that this somatic variant contributes to tumor behavior and progression.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 16

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the cellular responses to PLX4032 therapy and mentions the activation of downstream ERK targets in relation to the BRAFV600E variant, indicating a correlation with treatment response. Oncogenic: The BRAFV600E variant is implicated in the inhibition of p90RSK activation in melanoma cells, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the R89L variant of RAF1 alters its ability to bind Ras-GTP and its activation in response to PLX4032, indicating a change in molecular function. Oncogenic: The R89L variant is described in the context of its activation and role in signaling pathways, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 3726:R89L

Genes: 3726

Variants: R89L

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the activity of RAF1 kinase in relation to BRAFV600E and BRAFV600K variants, indicating that these variants alter the molecular function of RAF1, as evidenced by the observed kinase activity levels. Oncogenic: The mention of BRAFV600E and BRAFV600K in the context of non-detectable activity and their relationship to RAF1 activity suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 673:BRAFV600E 673:BRAFV600K

Genes: 673

Variants: BRAFV600E BRAFV600K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses the enzymatic activity of BRAF variants (BRAFV600E and BRAFV600K) and how their activity is altered by treatment with PLX4032, indicating a change in molecular function. Predictive: The mention of treatment with PLX4032 and its effect on the activity of BRAF variants suggests a correlation with response to therapy, indicating predictive evidence.

Gene→Variant (gene-first): 673:BRAFV600E 673:BRAFV600K

Genes: 673

Variants: BRAFV600E BRAFV600K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 8

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of melanoma cells with the BRAFV600E variant to the drug PLX4032, indicating a correlation with treatment sensitivity. Oncogenic: The BRAFV600E variant is implicated in the context of melanoma cells, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses changes in the phosphorylation state of ERK1/2 in response to treatment, indicating that the BRAFV600E variant alters the molecular function of these proteins in melanoma cells. Oncogenic: The mention of the BRAFV600E variant in the context of melanoma cells suggests that it contributes to tumor development or progression, as it is associated with changes in signaling pathways relevant to cancer.

Gene→Variant (gene-first): 673:BRAFV600E

Genes: 673

Variants: BRAFV600E

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the effects of PLX4032 on BRAFV600E/K melanoma cells, indicating a correlation between the variant and response to the therapy, specifically in terms of ERK1/2 phosphorylation. Oncogenic: The mention of BRAFV600E/K in the context of melanoma cells suggests that these somatic variants contribute to tumor development or progression, as they are associated with the activation of the RAF-MEK-ERK pathway in cancer.

Gene→Variant (gene-first): 673:BRAFV600K 673:V600E/K

Genes: 673

Variants: BRAFV600K V600E/K

[Paragraph-level] PMCID: PMC2848976 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of BRAF mutant melanoma cell strains, including those with the V600E mutation, to the drug PLX4032, indicating a correlation between the variant and response to therapy. Oncogenic: The V600E variant is mentioned in the context of BRAF mutations in melanoma cells, suggesting its role in tumor development or progression as part of the BRAF mutation profile.

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E

[Paper-level Aggregated] PMCID: PMC2837563

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The K-Ras mutations, including G12V, G12D, G13D, Q61H, L19F, K117N, and A146T, were shown to have transforming potential in NIH3T3 cells, indicating their role in promoting oncogenesis. Functional: The study assessed the functional impact of K-Ras mutations through focus formation assays and GTPase activity, demonstrating that certain mutations are in the active GTP-bound conformation and influence gene expression. Predictive: The presence of specific K-Ras mutations, such as A146T and K117N, was associated with phenotypes similar to known activating mutations, suggesting their potential to predict tumor behavior and response to therapies.

Gene→Variant (gene-first): KRAS(3845):A to C KRAS(3845):Ala to Thr KRAS(3845):Arg to Gln KRAS(3845):C to T KRAS(3845):G to A KRAS(3845):Lys to Asn BRAF(673):V600E KRAS(3845):aspartic acid residue at codon 173 KRAS(3845):A146T KRAS(3845):G12C KRAS(3845):G12D KRAS(3845):G12V KRAS(3845):G13D KRAS(3845):K117N KRAS(3845):L19F KRAS(3845):R164Q KRAS(3845):Q61H KRAS(3845):Ala146Thr KRAS(3845):Arg164Gln KRAS(3845):Leu19Phe KRAS(3845):Lys117Asn BRAF(673):G57T

Genes: KRAS(3845) BRAF(673)

Variants: A to C Ala to Thr Arg to Gln C to T G to A Lys to Asn V600E aspartic acid residue at codon 173 A146T G12C G12D G12V G13D K117N L19F R164Q Q61H Ala146Thr Arg164Gln Leu19Phe Lys117Asn G57T

[Paper-level Aggregated] PMCID: PMC2830973

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The variant JAK3V674A is described as an activating allele that transforms BaF3 cells to IL-3-independent growth, indicating its role in promoting oncogenic processes. Functional: The study demonstrates that JAK3V674A leads to increased viability of BaF3 cells in the absence of IL-3, and that inhibition of JAK3 activity by NSC114792 decreases cell viability, showing a functional consequence of the variant.

Gene→Variant (gene-first): JAK3(3718):V674A AKT1(207):serine/threonine

Genes: JAK3(3718) AKT1(207)

Variants: V674A serine/threonine

[Paragraph-level] PMCID: PMC2830973 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses the effects of the compound NSC114792 on the phosphorylation state of serine/threonine kinases, indicating that it alters molecular function related to these kinases.

Gene→Variant (gene-first): 207:serine/threonine

Genes: 207

Variants: serine/threonine

[Paragraph-level] PMCID: PMC2830973 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The variant JAK3V674A is described as an activating allele that can transform a lymphoid pro-B-cell line, indicating its role in tumor development or progression. Predictive: The passage discusses how treatment with the compound NSC114792 inhibits JAK3 activity and decreases the viability of BaF3-JAK3V674A cells, suggesting a correlation with response to therapy.

Gene→Variant (gene-first): 3718:V674A

Genes: 3718

Variants: V674A

[Paper-level Aggregated] PMCID: PMC2789045

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The evidence indicates that mutations S249C, Y375C, and K652E in FGFR3 lead to increased cell proliferation, morphological transformation, and anchorage-independent growth, suggesting that these mutations contribute to oncogenic processes in bladder tumors. Functional: The study demonstrates that the FGFR3 mutations affect signaling pathways and cellular behaviors, such as phosphorylation of downstream effectors and changes in cell cycle profiles, indicating a functional impact of these mutations on urothelial cells. Predictive: The differential effects of the FGFR3 mutations on cell proliferation and viability suggest that the presence of specific mutations like S249C and Y375C may predict the behavior of bladder cancer cells in response to growth conditions and treatments.

Gene→Variant (gene-first): FGFR3(2261):K652E FGFR3(2261):S249C FGFR3(2261):Y375C FGFR3(2261):Y762F

Genes: FGFR3(2261)

Variants: K652E S249C Y375C Y762F

[Paper-level Aggregated] PMCID: PMC2766370

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The text describes the use of LCN-HRM and sequencing to identify specific mutations (c.34G>T and delE746_A750) in DNA samples, indicating that these methods are employed for diagnostic purposes to detect the presence of these variants. Oncogenic: The presence of mutations such as c.34G>T (p.G12C) and delE746_A750 in EGFR is associated with oncogenic activity in non-small cell lung cancer (NSCLC), suggesting that these variants contribute to cancer development.

Gene→Variant (gene-first): KRAS(3845):c.34G>T KRAS(3845):p.G12C KRAS(3845):c.38G>A KRAS(3845):delE746_A750 EGFR

Genes: KRAS(3845)

Variants: c.34G>T p.G12C c.38G>A delE746_A750 EGFR

[Paper-level Aggregated] PMCID: PMC2736831

Evidence Type(s): Predictive, Prognostic

Justification: Predictive: The BRAF V600E mutation has been associated with resistance to treatment, indicating its role in predicting treatment outcomes in patients receiving anti-EGFR monoclonal antibodies. Prognostic: The presence of the BRAF V600E mutation was linked to significantly shorter overall survival (OS) and a trend towards shorter progression-free survival (PFS), suggesting its prognostic value in the study population.

Gene→Variant (gene-first): BRAF(673):V600E

Genes: BRAF(673)

Variants: V600E

[Paragraph-level] PMCID: PMC2736831 Section: ABSTRACT PassageIndex: 8

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The mention of BRAF V600E mutations in the context of optimizing patient selection for anti-EGFR monoclonal antibodies indicates a correlation with treatment response. Diagnostic: The assessment of BRAF V600E mutations suggests its role in defining or classifying patients for treatment, indicating its use as a biomarker in the context of disease.

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E

[Paragraph-level] PMCID: PMC2736831 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses the role of the BRAF V600E mutation in predicting resistance to cetuximab plus irinotecan, indicating a correlation with treatment response. Diagnostic: The mention of BRAF V600E mutations in the context of a specific cohort of KRAS wild-type patients suggests its use in classifying or defining a subset of patients for treatment.

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E

[Paragraph-level] PMCID: PMC2736831 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The BRAF V600E mutation is mentioned in the context of predicting resistance to anti-EGFR monoclonal antibodies in metastatic colorectal cancer. Diagnostic: The BRAF V600E mutation is associated with resistance, indicating its role in defining or classifying a specific disease context (metastatic colorectal cancer).

Gene→Variant (gene-first): 673:V600E

Genes: 673

Variants: V600E

[Paper-level Aggregated] PMCID: PMC2670982

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The presence of somatic mutations, including L914F, which cause ligand-independent hyperphosphorylation and abnormal cellular responses, indicates a role in tumorigenesis related to venous malformations. Functional: The L914F mutation demonstrated abnormal localization and response to ligand when overexpressed in HUVECs, indicating a functional alteration in the receptor's activity.

Gene→Variant (gene-first): ANGPT1(284):L914F TEK(7010):R849W

Genes: ANGPT1(284) TEK(7010)

Variants: L914F R849W

[Paragraph-level] PMCID: PMC2670982 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Oncogenic, Functional

Justification: Predisposing: The passage describes germline substitutions in the TIE2/TEK receptor that cause a rare inherited form of venous anomalies, indicating that these variants confer inherited risk for developing the disease. Oncogenic: The passage discusses somatic mutations in TIE2 that contribute to tumor development, specifically noting the identification of somatic mutations in lesions and their role in the etiology of sporadic venous malformations. Functional: The passage mentions that the L914F variant shows ligand-independent hyperphosphorylation and abnormal localization when overexpressed, indicating that it alters molecular function.

Gene→Variant (gene-first): 284:L914F 7010:R849W

Genes: 284 7010

Variants: L914F R849W

[Paper-level Aggregated] PMCID: PMC2570525

Evidence Type(s): Oncogenic, Diagnostic, Functional

Justification: Oncogenic: The AKT1 E17K and AKT3 E17K mutations are described as activating mutations that lead to increased AKT phosphorylation, indicating their role in promoting cancer cell growth and survival. Diagnostic: The study utilized mass spectroscopy-based mutation detection to identify AKT1 E17K and AKT3 E17K mutations in melanoma specimens, demonstrating the potential for these mutations to serve as biomarkers for melanoma diagnosis. Functional: The expression of AKT3 E17K in human melanoma cells resulted in increased AKT phosphorylation, indicating that this mutation has a functional impact on cellular signaling pathways involved in cancer.

Gene→Variant (gene-first): AKT1(207):AKT1 (E17K AKT1(207):E17K AKT1(207):AKT1 E17K

Genes: AKT1(207)

Variants: AKT1 (E17K E17K AKT1 E17K

[Paragraph-level] PMCID: PMC2570525 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage describes how the AKT1 E17K variant alters molecular function by increasing AKT phosphorylation in NIH 3T3 cells and A375 human melanoma cells, indicating a change in biochemical activity. Oncogenic: The evidence suggests that the AKT1 E17K variant contributes to tumor development or progression, as it is expressed in a melanoma cell line and leads to increased AKT phosphorylation, which is often associated with oncogenic processes.

Gene→Variant (gene-first): 207:AKT1 E17K 207:E17K

Genes: 207

Variants: AKT1 E17K E17K

[Paragraph-level] PMCID: PMC2570525 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the E17K mutation activates AKT3, suggesting that it alters molecular or biochemical function.

Gene→Variant (gene-first): 207:E17K

Genes: 207

Variants: E17K

[Paragraph-level] PMCID: PMC2570525 Section: RESULTS PassageIndex: 4

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 207:AKT1 E17K 207:E17K

Genes: 207

Variants: AKT1 E17K E17K

[Paragraph-level] PMCID: PMC2570525 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of the E17K mutation in clinical specimens, indicating its association with melanoma and its presence in metastatic lesions, which supports its use in defining or classifying the disease. Oncogenic: The E17K mutation is described as being present in metastatic lesions, suggesting that it contributes to tumor development or progression in melanoma.

Gene→Variant (gene-first): 207:E17K

Genes: 207

Variants: E17K

[Paragraph-level] PMCID: PMC2570525 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage mentions the detection of AKT1 E17K mutations in melanoma, indicating that the variant is associated with a specific disease (melanoma). Oncogenic: The mention of AKT1 E17K mutations in the context of melanoma suggests that this somatic variant may contribute to tumor development or progression.

Gene→Variant (gene-first): 207:AKT1 E17K 207:E17K

Genes: 207

Variants: AKT1 E17K E17K

[Paper-level Aggregated] PMCID: PMC2360265

Evidence Type(s): Predictive, Oncogenic, Prognostic

Justification: Predictive: The text indicates that classical mutations in the EGFR tyrosine kinase domain are associated with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with NSCLC, suggesting that these mutations can predict treatment response. Oncogenic: The presence of EGFR mutations, including E746V, G719D, and L858R, is implied to have a role in tumorigenesis, as they are described as somatic mutations found in tumor tissues, indicating their potential oncogenic nature. Prognostic: The text discusses median time to tumor progression (TTP) and overall survival (OS) in relation to different EGFR mutation statuses, suggesting that these mutations may have prognostic implications for patient outcomes.

Gene→Variant (gene-first): EGFR(1956):E746V EGFR(1956):G719D EGFR(1956):L858R EGFR(1956):G719X

Genes: EGFR(1956)

Variants: E746V G719D L858R G719X

[Paper-level Aggregated] PMCID: PMC1952070

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The L858R mutation in exon 21 is a well-known oncogenic mutation associated with non-small cell lung cancer and has been previously correlated with gefitinib sensitivity, although in this study it was found in a non-responder. Predictive: The presence of mutations in the EGFR tyrosine kinase domain, including L858R, has been previously associated with response to gefitinib, indicating a potential predictive value for treatment outcomes.

Gene→Variant (gene-first): TXK(7294):G/A NA:rs10251977 NA:rs17290643 EGFR(1956):L858R EGFR(1956):T790M

Genes: TXK(7294) NA EGFR(1956)

Variants: G/A rs10251977 rs17290643 L858R T790M

[Paragraph-level] PMCID: PMC1952070 Section: RESULTS PassageIndex: 8

Evidence Type(s): Diagnostic, Predictive

Justification: Diagnostic: The passage mentions the detection of single nucleotide polymorphisms (SNPs) and their association with specific exons, indicating their role in defining or classifying genetic variants. Predictive: The passage explicitly states that there was "no correlation between these alleles and gefitinib response," which implies that the variants were evaluated for their predictive value regarding treatment response.

Gene→Variant (gene-first): 7294:G/A NA:rs10251977 NA:rs17290643

Genes: 7294 NA

Variants: G/A rs10251977 rs17290643

[Paragraph-level] PMCID: PMC1952070 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the correlation of the L858R mutation with gefitinib response, indicating that it is associated with treatment sensitivity or resistance. Oncogenic: The L858R mutation is described as a somatic mutation found in tumor samples, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 1956:L858R 1956:T790M

Genes: 1956

Variants: L858R T790M

[Paper-level Aggregated] PMCID: PMC1702556

Evidence Type(s): Oncogenic, Predictive, Diagnostic, Prognostic

Justification: Oncogenic: The presence of identical missense mutations in multiple patient samples and their oncogenicity in transformation assays suggest that these mutants play a role in gliomagenesis. Predictive: The data indicate that EGFR missense mutants sensitize transformed cells to EGFR kinase inhibitors, suggesting their potential as predictive biomarkers for response to therapy. Diagnostic: The identification of specific EGFR missense mutations in glioblastoma samples supports their use as diagnostic markers for this type of cancer. Prognostic: The association of certain EGFR mutations with clinical responses to EGFR kinase inhibitors implies that these mutations may have prognostic significance in glioblastoma treatment outcomes.

Gene→Variant (gene-first): EGFR(1956):A289 EGFR(1956):A289D EGFR(1956):A289T EGFR(1956):E330K EGFR(1956):L861Q EGFR(1956):R108 EGFR(1956):R324L EGFR(1956):A289V EGFR(1956):G598V EGFR(1956):R108K EGFR(1956):T263P EGFR(1956):L858R EGFR(1956):T790M

Genes: EGFR(1956)

Variants: A289 A289D A289T E330K L861Q R108 R324L A289V G598V R108K T263P L858R T790M

[Paper-level Aggregated] PMCID: PMC1240052

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text describes how mutations such as L858R and G719S in the EGFR gene can transform NIH-3T3 cells, leading to anchorage independence and tumor formation in immunocompromised mice, indicating their oncogenic potential. Predictive: The presence of activating EGFR mutations, including L858R and G719S, is associated with clinical responses to EGFR inhibitors like gefitinib and erlotinib in lung adenocarcinoma patients, suggesting these mutations can predict treatment outcomes. Functional: The study demonstrates that mutant EGFRs, including L858R and G719S, exhibit constitutive activation of downstream signaling pathways, such as STAT3 and Akt, indicating functional alterations in signaling due to these mutations.

Gene→Variant (gene-first): EGFR(1956):A750P EGFR(1956):D770_N771insNPG EGFR(1956):E749del EGFR(1956):G719S EGFR(1956):L858R EGFR(1956):L747_E749del A750P HRAS(3265):V12 EGFR(1956):D837A AKT1(207):serine/threonine

Genes: EGFR(1956) HRAS(3265) AKT1(207)

Variants: A750P D770_N771insNPG E749del G719S L858R L747_E749del A750P V12 D837A serine/threonine

[Paragraph-level] PMCID: PMC7211323 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the ACVR2A variants (including c.285delA) affect the expression and stability of the ACVR2A protein, indicating that these variants alter molecular function. Oncogenic: The context of the study involves the role of ACVR2A mutations in gastric cancer (GC) cell lines, suggesting that these somatic variants may contribute to tumor development or progression.

Gene→Variant (gene-first): 92:1310AA 92:c.285delA

Genes: 92

Variants: 1310AA c.285delA

[Paragraph-level] PMCID: PMC7211323 Section: RESULTS PassageIndex: 9

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the mutation rate of ACVR2A in a specific population and identifies specific mutations as frequent occurrences in gastric cancer patients, indicating their association with the disease. Oncogenic: The passage describes nonsynonymous mutations in the ACVR2A gene that lead to protein changes, specifically mentioning frameshift truncating mutations, which contribute to tumor development in gastric cancer.

Gene→Variant (gene-first): 92:1310delA 92:c.1309-1310delAA 92:c.285delA 92:p. D96Tfs*54

Genes: 92

Variants: 1310delA c.1309-1310delAA c.285delA p. D96Tfs*54

[Paragraph-level] PMCID: PMC7211323 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the association of specific mutations (c.1310delA, 1309-1310delAA, c.285delA) with the MSI-H subtype of gastric cancers, indicating their role in defining or classifying the disease. Oncogenic: The variants mentioned are associated with a high mutation frequency and a high MSI score, suggesting their contribution to tumor development or progression in gastric cancer.

Gene→Variant (gene-first): 92:1309-1310delAA 92:c.1310delA 92:c.285delA

Genes: 92

Variants: 1309-1310delAA c.1310delA c.285delA

In my experience, finding the symptoms of deep-rooted problems is one of the easiest things in education. One of the hardest things to do when teaching is correctly diagnosing what to do to fix those symptoms. That mission requires self-reflection and playback, especially when dealing with behavioral issues.

[Paragraph-level] PMCID: PMC6549573 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic

Justification: Oncogenic: The presence of the KRAS G12D mutation is discussed in the context of tumor analysis, indicating its role in contributing to tumor development or progression, particularly as it is mentioned alongside other mutations in a patient with no observed responses.

Gene→Variant (gene-first): 3845:G12D

Genes: 3845

Variants: G12D

[Paragraph-level] PMCID: PMC6549573 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The passage discusses the KRAS G12D variant in the context of tumor regression and survival in specific mouse models, indicating its role in tumor development or progression. Prognostic: The mention of prolonged survival in the context of the KRAS G12D variant suggests a correlation with disease outcome, independent of therapy.

Gene→Variant (gene-first): 3845:G12D

Genes: 3845

Variants: G12D

[Paragraph-level] PMCID: PMC6549573 Section: RESULTS PassageIndex: 8

Evidence Type(s): Predictive, Diagnostic, Oncogenic

Justification: Predictive: The passage discusses the response to bortezomib in patients with KRAS G12D-mutant lung adenocarcinomas, indicating a correlation between the variant and treatment response. Diagnostic: The KRAS G12D mutation is identified through molecular profiling as part of the patient's diagnosis, linking the variant to the classification of the disease. Oncogenic: The KRAS G12D mutation is described in the context of tumor development and progression, as it is a known driver mutation in lung adenocarcinomas.

Gene→Variant (gene-first): 3845:G12D

Genes: 3845

Variants: G12D

[Paragraph-level] PMCID: PMC6549573 Section: RESULTS PassageIndex: 4

Evidence Type(s): Predictive, Diagnostic, Oncogenic

Justification: Predictive: The passage discusses the response of patients with KRAS G12D-mutant lung cancers to bortezomib, indicating a correlation between the variant and treatment response. Diagnostic: The mention of KRAS G12D in the context of lung cancers suggests its role in classifying or defining a specific subtype of the disease. Oncogenic: The variant KRAS G12D is implicated in lung cancers, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): 3845:G12D

Genes: 3845

Variants: G12D

[Paragraph-level] PMCID: PMC6549573 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Diagnostic, Oncogenic

Justification: Predictive: The passage discusses patients with KRAS G12D-mutant lung cancers treated with bortezomib, indicating a correlation between the variant and response to therapy. Diagnostic: The mention of "KRAS G12D-mutant lung cancers" suggests that the variant is used to classify or define a specific subtype of lung cancer. Oncogenic: The variant KRAS G12D is implicated in the context of lung adenocarcinoma, indicating its role in tumor development or progression.

Gene→Variant (gene-first): 3845:G12D

Genes: 3845

Variants: G12D

[Paragraph-level] PMCID: PMC6173734 Section: RESULTS PassageIndex: 2

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage describes a pathogenic TP53 missense variant c.422G>A (p.Cys141Tyr) in the context of tumor development, indicating its contribution to tumor progression through the loss of heterozygosity and clonal biallelic loss of TP53.

Gene→Variant (gene-first): 7157:c.422G>A 7157:p.Cys141Tyr

Genes: 7157

Variants: c.422G>A p.Cys141Tyr

[Paragraph-level] PMCID: PMC7182441 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant SLC6A14 affects amino acid transport and starvation, indicating that the blockade of its function alters molecular processes such as the expression of specific markers and the phosphorylation status of mTOR and S6 kinase. Oncogenic: The variant SLC6A14 is implicated in tumor behavior, as the study evaluates its role in colon cancer cell lines, suggesting that it contributes to tumor development or progression through its function in amino acid transport and mTOR signaling.

Gene→Variant (gene-first): 6198:S6

Genes: 6198

Variants: S6

[Paragraph-level] PMCID: PMC8453302 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The variant G292R in HER2 is associated with a complete response to pyrotinib treatment in a patient with metastatic cervical adenocarcinoma, indicating its correlation with therapy response. Oncogenic: The passage discusses the HER2 G292R variant in the context of a metastatic cervical adenocarcinoma, suggesting that it contributes to tumor development or progression.

Gene→Variant (gene-first): 2064:G292R

Genes: 2064

Variants: G292R

[Paragraph-level] PMCID: PMC7064492 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of MAP2K1 (p.K57N) mutations in patients with auricular AVM, indicating an association with the condition and suggesting its role in defining or confirming the disease. Oncogenic: The presence of the MAP2K1 (p.K57N) mutation in the tissue adjacent to the cartilage suggests that it may contribute to tumor development or progression in the context of the auricular AVM.

Gene→Variant (gene-first): 5604:p.K57N

Genes: 5604

Variants: p.K57N

[Paragraph-level] PMCID: PMC4748120 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Predictive, Diagnostic

Justification: Oncogenic: The passage describes how the A66dup variant contributes to tumor development by transforming the growth of primary myeloid progenitors and Ba/F3 cells, indicating its role in oncogenesis. Predictive: The passage mentions that K-Ras proteins with the A66dup variant are hypersensitive to MEK inhibition, suggesting a correlation with response to a specific therapy. Diagnostic: The discovery of the A66dup variant in a child with an atypical myeloproliferative neoplasm suggests its potential use in defining or classifying this disease.

Gene→Variant (gene-first): 5295:A66dup

Genes: 5295

Variants: A66dup

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the Ezh2Y641F mutation alters the molecular function of the enzyme, specifically its effect on H3K27me3 distribution, indicating a change in biochemical activity. Oncogenic: The context of the study involves analyzing the Ezh2Y641F mutation in melanoma cell lines, suggesting that this somatic variant contributes to tumor development or progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 22

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the Ezh2Y641F variant affects the H3K27me3 signal around the transcription start site and gene body, indicating an alteration in molecular function related to gene expression regulation. Oncogenic: The variant Ezh2Y641F is associated with changes in gene expression in cancer cell lines, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 21

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the Ezh2Y641F variant alters the distribution of H3K27me3, indicating a change in molecular function related to gene expression and chromatin modification.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the Ezh2Y641F variant alters the expression of numerous transcripts in B-cells and melanoma cells, indicating a change in molecular function related to gene expression. Oncogenic: The variant Ezh2Y641F is associated with melanoma cell lines derived from tumors, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 13

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the anti-tumor efficacy of EZH2 inhibitors and their effects on tumor growth inhibition in Ezh2Y641F/+ tumors, indicating a correlation with treatment response. Oncogenic: The variant Ezh2Y641F is implicated in tumor development, as it is studied in the context of autochthonous tumors in mice, suggesting its role in contributing to tumor progression.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the response of melanoma cell lines with the Y641F variant to various EZH2 inhibitors, indicating a correlation between the variant and sensitivity to treatment. Functional: The passage describes how the Y641F variant affects the potency of the JQEZ5 inhibitor, demonstrating that the variant alters the molecular function of EZH2 in the context of drug response.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

Genes: 2146

Variants: Y641F Y646F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 10

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the oncogenic effects of the B-RAFV600E and Ezh2Y641F mutations in the context of melanoma formation, indicating that these variants contribute to tumor development or progression. Functional: The passage describes how the presence of the Y641F mutation does not alter the expression of certain genes, suggesting that it may affect molecular or biochemical functions related to oncogenic pathways.

Gene→Variant (gene-first): 673:B-RAFV600E 2146:Y641F

Genes: 673 2146

Variants: B-RAFV600E Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the role of B-RafV600E and Ezh2Y641F in promoting melanoma, indicating that these variants contribute to tumor development or progression. Functional: The mention of B-Raf as a downstream effector of N-RAS signaling suggests that the variant B-RafV600E alters molecular function in the context of signaling pathways involved in melanoma.

Gene→Variant (gene-first): 673:B-RafV600E 2146:Y641F

Genes: 673 2146

Variants: B-RafV600E Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 8

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the Ezh2Y641F mutation cooperates with the B-RAFV600E mutation to accelerate tumorigenesis in melanoma, indicating that it contributes to tumor development. Functional: The passage implies that the Ezh2Y641F mutation alters the tumorigenic process in conjunction with B-RAFV600E, suggesting a change in molecular function related to tumor maintenance and formation.

Gene→Variant (gene-first): 673:B-RAFV600E 673:B-RafV600E 2146:Y641F

Genes: 673 2146

Variants: B-RAFV600E B-RafV600E Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the EZH2Y641F variant exhibits altered methylase activity, indicating that the variant affects molecular function. Oncogenic: The evidence suggests that the EZH2Y641F mutation contributes to tumor development, as demonstrated by the tumorigenesis observed in mice harboring this mutation.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646 2146:tyrosine to phenylalanine

Genes: 2146

Variants: Y641F Y646 tyrosine to phenylalanine

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the Ezh2Y641F variant contributes to tumor formation in B-cell lymphomas, indicating its role in tumor development and progression. Functional: The variant is associated with altered molecular function, specifically in the context of its cooperation with other genetic alterations to influence B-cell transformation and apoptotic resistance.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The passage describes how the Ezh2Y641F variant contributes to the development of B-cell lymphoma in mice, indicating its role in tumor progression. Prognostic: The median survival of one year for mice with the Ezh2Y641F variant suggests a correlation with disease outcome, specifically survival, independent of therapy.

Gene→Variant (gene-first): 2146:Y641F

Genes: 2146

Variants: Y641F

[Paragraph-level] PMCID: PMC4899144 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the Y641F mutation alters the expression of Ezh2 transcripts and leads to a gain-of-function effect, evidenced by the increase in H3K27me3 levels in B-cells, indicating a change in molecular function. Oncogenic: The Y641F mutation is described as equivalent to a common EZH2 missense mutation found in human cancers, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 2146:Y641F 2146:Y646F

Genes: 2146

Variants: Y641F Y646F

[Paragraph-level] PMCID: PMC7074098 Section: RESULTS PassageIndex: 9

Evidence Type(s): Prognostic

Justification: Prognostic: The passage discusses the correlation of BAP1 mutations and copy number variations with overall survival in cutaneous melanoma (CM), indicating that certain alterations are associated with better survival outcomes.

Gene→Variant (gene-first): 8314:E30K 8314:I643T 8314:L416F 8314:P629S 8314:R417M 8314:R59W 6490:S143N

Genes: 8314 6490

Variants: E30K I643T L416F P629S R417M R59W S143N

[Paragraph-level] PMCID: PMC8033310 Section: RESULTS PassageIndex: 11

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the frequency of PIK3CA mutations, including E545K and H1047R, in patients with triple-negative breast cancer (TNBC), indicating their association with the diagnosis of invasive cancer. Oncogenic: The presence of PIK3CA mutations, specifically E545K and H1047R, in patients with invasive cancer suggests that these somatic variants contribute to tumor development or progression in the context of TNBC.

Gene→Variant (gene-first): 5290:E545K 5290:H1047R

Genes: 5290

Variants: E545K H1047R

[Paragraph-level] PMCID: PMC8033310 Section: RESULTS PassageIndex: 6

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the PIK3CA mutation, including E545K, induces resistance to chemotherapy, indicating a correlation with treatment response. Oncogenic: The variant E545K is implicated in tumor development and progression, as evidenced by the experimental results showing increased tumor volume in the presence of this mutation.

Gene→Variant (gene-first): 5290:E545K

Genes: 5290

Variants: E545K

[Paragraph-level] PMCID: PMC8033310 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how the PIK3CA E545K mutation affects the sensitivity of TNBC cells to chemotherapy, specifically noting that cells with this mutation became less sensitive to the chemotherapeutic agent epirubicin. Oncogenic: The passage indicates that the PIK3CA E545K mutation promotes growth and inhibits apoptosis in TNBC cell lines, suggesting its role in tumor development and progression.

Gene→Variant (gene-first): 5290:E545K

Genes: 5290

Variants: E545K

[Paragraph-level] PMCID: PMC8033310 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the PIK3CA mutation, including E545K, contributes to enhanced cell proliferation, reduced apoptosis, and increased aggressiveness in TNBC cells, indicating its role in tumor development or progression. Functional: The passage describes how the PIK3CA mutation alters the behavior of TNBC cells, specifically in terms of cell cycle progression and apoptosis, suggesting that the variant affects molecular or biochemical functions.

Gene→Variant (gene-first): 5290:E545K

Genes: 5290

Variants: E545K

[Paragraph-level] PMCID: PMC11272140 Section: RESULTS PassageIndex: 10

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the overall response rate (ORR) of patients with specific ROS1 mutations, including G2032R, in relation to treatment with taletrectinib, indicating a correlation with treatment response. Oncogenic: The presence of ROS1 resistance mutations, including G2032R, L2026M, S1986F, and G2101A, suggests that these somatic variants contribute to tumor development or progression, particularly in the context of resistance to crizotinib.

Gene→Variant (gene-first): 6098:G2032R 4914:G2101A 7294:L2026M 7294:S1986F

Genes: 6098 4914 7294

Variants: G2032R G2101A L2026M S1986F

[Paragraph-level] PMCID: PMC4868698 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of the JAK1S703I mutant PDX model to the treatment of a JAK1/2 inhibitor, ruxolitinib, indicating a correlation with response to therapy. Oncogenic: The JAK1S703I mutation is described as activating the JAK-STAT signaling pathway and driving cell proliferation, which suggests its contribution to tumor development or progression.

Gene→Variant (gene-first): 3716:S703I

Genes: 3716

Variants: S703I

[Paragraph-level] PMCID: PMC10524391 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response rate and disease control rate of patients treated with osimertinib and selpercatinib, indicating that the variants mentioned (C797S, G12S, G810S, V600E) are associated with treatment response and resistance mechanisms. Oncogenic: The variants C797S, G12S, G810S, and V600E are described in the context of resistance mechanisms, suggesting their role in tumor development or progression in the setting of lung cancers.

Gene→Variant (gene-first): 1956:C797S 3845:G12S 5979:G810S 1956:T790M 673:V600E

Genes: 1956 3845 5979 673

Variants: C797S G12S G810S T790M V600E

[Paragraph-level] PMCID: PMC10524391 Section: RESULTS PassageIndex: 26

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses resistance mechanisms related to specific variants, indicating their correlation with treatment response, particularly in the context of on-target and off-target resistance. Oncogenic: The variants mentioned are associated with resistance mechanisms that contribute to tumor development or progression, as they are involved in co-occurring resistance mechanisms in cancer cases.

Gene→Variant (gene-first): 1956:C797S 3845:G12S 5979:G810S 673:V600E 5979:V804E 5979:V804M

Genes: 1956 3845 5979 673

Variants: C797S G12S G810S V600E V804E V804M

[Paragraph-level] PMCID: PMC10524391 Section: RESULTS PassageIndex: 25

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses hotspot mutations BRAF V600E and KRAS G12S being found in cases of off-target resistance, indicating that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:G12S 673:V600E

Genes: 3845 673

Variants: G12S V600E

[Paragraph-level] PMCID: PMC10524391 Section: RESULTS PassageIndex: 24

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses an acquired RET G810S mutation in the context of tumor progression, indicating that this somatic variant may contribute to tumor development or progression.

Gene→Variant (gene-first): 5979:G810S

Genes: 5979

Variants: G810S

[Paragraph-level] PMCID: PMC10524391 Section: RESULTS PassageIndex: 23

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses resistance mutations that affect the engagement of therapeutic EGFR or RET kinases, indicating a correlation with resistance to specific therapies. Oncogenic: The variants mentioned (C797S, T790M, V804M/E, G810S) are described as resistance mutations that contribute to tumor progression by impacting kinase engagement, suggesting their role in oncogenesis.

Gene→Variant (gene-first): 1956:C797S 5979:G810S 1956:T790M 5979:V804M/E

Genes: 1956 5979

Variants: C797S G810S T790M V804M/E

[Paragraph-level] PMCID: PMC10524391 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses the presence of the EGFR T790M mutation in patients who had received prior EGFR-directed therapy, indicating a correlation with treatment response or resistance to osimertinib. Diagnostic: The mention of the EGFR T790M mutation being detectable at the time of study enrollment suggests its role in classifying or confirming the disease status in patients undergoing treatment.

Gene→Variant (gene-first): 1956:T790M

Genes: 1956

Variants: T790M

[Paragraph-level] PMCID: PMC10524391 Section: RESULTS PassageIndex: 8

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage indicates that the variants L747S, L858R, and T790M are present in tumors, suggesting their role in tumor development or progression. Diagnostic: The presence of specific EGFR mutations, including L747S, L858R, and T790M, is used to classify the tumors, indicating their association with the disease.

Gene→Variant (gene-first): 1956:L747S 1956:L858R 1956:T790M

Genes: 1956

Variants: L747S L858R T790M

[Paragraph-level] PMCID: PMC5615879 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of KIT mutations in cases and specifies the types of mutations found in different exons, indicating their association with the disease. Oncogenic: The mention of KIT mutations contributing to tumor development is implied by their prevalence in cases, suggesting a role in cancer progression.

Gene→Variant (gene-first): 3815:Ala-Tyr 3815:c.1509_1510insACCTAT 728378:c.1666C>G 3815:c.1666_1668dupCAG 3815:c.1672_1677delAAGGTTinsAGT 5156:c.1925A>G 3815:p.K558_V559delinsS 728378:p.K642R 728378:p.Q556E 3815:p.Q556dup 3815:p.Y503_F504insTY

Genes: 3815 728378 5156

Variants: Ala-Tyr c.1509_1510insACCTAT c.1666C>G c.1666_1668dupCAG c.1672_1677delAAGGTTinsAGT c.1925A>G p.K558_V559delinsS p.K642R p.Q556E p.Q556dup p.Y503_F504insTY