[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the G101V mutation alters drug binding by changing the molecular interactions within the BCL-2 structure, indicating an alteration in biochemical function. Predictive: The evidence suggests that the G101V mutation impacts the binding affinity of venetoclax, which correlates with the response to this specific therapy.

Gene→Variant (gene-first): 596:E152 596:G101 596:G101A 596:G101V

Genes: 596

Variants: E152 G101 G101A G101V

[Paragraph-level] PMCID: PMC6547681 Section: RESULTS PassageIndex: 3

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 596:F104

Genes: 596

Variants: F104

[Paragraph-level] PMCID: PMC2360265 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses the association of classical mutations, including G719X and L858R, with sensitivity to tyrosine kinase inhibitors (TKIs) in patients with NSCLC, indicating a correlation with treatment response. Diagnostic: The mention of classical mutations in the EGFR tyrosine kinase domain being associated with sensitivity to TKIs suggests that these variants can be used to classify or define a subtype of disease in NSCLC patients.

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

Genes: 1956

Variants: G719X L858R

[Paragraph-level] PMCID: PMC3219854 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage describes a missense point mutation (Trp557Gly) identified in the KIT gene associated with neurofibromatosis type 1-related gastrointestinal stromal tumors (GISTs), indicating its contribution to tumor development. Diagnostic: The variant Trp557Gly is mentioned in the context of identifying and characterizing the tumors associated with neurofibromatosis type 1, suggesting its role in defining the disease subtype.

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

Genes: 3815

Variants: Trp557Gly

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 12

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the identification of rare germline variants (V37M, R181H) in patients with B-ALL, indicating their association with the disease. Functional: Luciferase assays performed on the variants showed no significant changes in transcriptional repression activity compared to WT ETV6, indicating an assessment of their molecular function.

Gene→Variant (gene-first): 2120:11905459G>A 2120:12022436 G>A 2120:R181H 2120:V37M 2120:rs150089916

Genes: 2120

Variants: 11905459G>A 12022436 G>A R181H V37M rs150089916

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Justification: Functional: The detection of different localization patterns for the mutants P214L, R369Q, and R399C also suggests alterations in their molecular or biochemical function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs 2120:P214L 2120:R369Q 2120:R399C

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the mutations L349P, N385fs, P214L, R369Q, and R399C impair the transcriptional repression function of ETV6, indicating that these variants alter molecular function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs 2120:P214L 2120:R369Q 2120:R399C

Genes: 2120

Variants: L349P N385fs P214L R369Q R399C

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the L349P and N385fs mutations are predicted to alter the molecular function of the ETV6 protein, including conformational changes and truncation that affect DNA interaction.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs

Genes: 2120

Variants: L349P N385fs

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 6

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the identification of a heterozygous deletion in ETV6 that is associated with the diagnosis of acute lymphoblastic leukemia (ALL) in the proband, indicating its role in defining the disease. Oncogenic: The variant N385fs is described as leading to a truncation of the ETV6 protein, which is implicated in tumor development, specifically in the context of acute lymphoblastic leukemia (ALL).

Gene→Variant (gene-first): 2120:N385fs 2120:c.1153-5_1153_1delAACAG

Genes: 2120

Variants: N385fs c.1153-5_1153_1delAACAG

[Paragraph-level] PMCID: PMC4477877 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Predisposing, Oncogenic

Justification: Diagnostic: The variant 415 T>C is associated with thrombocytopenia and leukemia, as it was identified in all affected family members and absent in unaffected individuals, indicating its role in defining the disease. Predisposing: The passage describes the variant as being present in affected individuals and absent in unaffected individuals, suggesting it confers inherited risk for developing the disease, although it does not explicitly state that it is germline. Oncogenic: The variant is described in the context of leukemia, indicating its potential role in tumor development or progression, particularly as it is a missense mutation in a gene associated with leukemia.

Gene→Variant (gene-first): 10320:415 T>C 2120:L349P 2120:c. T1046C 2120:proline for leucine at codon 349

Genes: 10320 2120

Variants: 415 T>C L349P c. T1046C proline for leucine at codon 349

[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Predisposing, Functional

Justification: Predisposing: The passage discusses inherited mutations in ETV6 that confer susceptibility to acute leukemia, indicating a germline origin and inherited risk for developing the disease. Functional: The passage describes how the ETV6 mutations (L349P and N385fs) alter the protein's localization and its ability to regulate gene expression, demonstrating a change in molecular function.

Gene→Variant (gene-first): 2120:L349P 2120:N385fs

Genes: 2120

Variants: L349P N385fs

[Paragraph-level] PMCID: PMC4477877 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predisposing, Oncogenic, Functional

Justification: Predisposing: The passage describes a germline ETV6 p. L349P mutation identified in a kindred affected by thrombocytopenia and ALL, indicating an inherited risk for developing the disease. Oncogenic: The ETV6 p. N385fs mutation was found in leukemic cells and is associated with the deletion of wild type ETV6, suggesting its contribution to tumor development in the context of leukemia. Functional: The enforced expression of the ETV6 mutants showed impaired nuclear localization and a significantly reduced ability to regulate the transcription of ETV6 target genes, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2120:p. L349P 2120:p. N385fs

Genes: 2120

Variants: p. L349P p. N385fs

[Paragraph-level] PMCID: PMC8307492 Section: RESULTS PassageIndex: 18

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the T790M mutation as a mechanism of resistance to the EGFR inhibitor osimertinib, indicating its correlation with treatment response. Oncogenic: The T790M mutation is described as contributing to resistance in patients treated with EGFR inhibitors, suggesting its role in tumor progression.

Gene→Variant (gene-first): 1956:G719S 1956:L858R 1956:L861Q 1956:T790M

Genes: 1956

Variants: G719S L858R L861Q T790M

[Paragraph-level] PMCID: PMC8307492 Section: RESULTS PassageIndex: 17

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses overall survival (OS) outcomes associated with the L858R variant, indicating that it correlates with disease outcome independent of therapy. Diagnostic: The mention of the type of EGFR mutation, including L858R, being associated with overall survival suggests its role in classifying or defining disease outcomes.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC8307492 Section: RESULTS PassageIndex: 16

Evidence Type(s): Predictive, Prognostic

Justification: Predictive: The passage discusses the proportion of patients receiving first-line targeted therapy based on the presence of the L858R mutation, indicating a correlation with treatment response. Prognostic: The median overall survival (OS) for patients with the L858R mutation is reported, demonstrating its correlation with disease outcome independent of therapy.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC8307492 Section: RESULTS PassageIndex: 13

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses overall survival (OS) in patients with the L858R variant, indicating a correlation between this variant and disease outcome, independent of therapy. Diagnostic: The mention of distinct survival patterns observed in different EGFR mutation subclasses, including L858R, suggests that this variant is used to classify or define a subtype of disease.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC8307492 Section: RESULTS PassageIndex: 11

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC8307492 Section: RESULTS PassageIndex: 9

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the prevalence of EGFR mutations, including L858R and L861X, in patients at initial diagnosis, indicating their association with the disease and their use in defining the mutation status of patients. Oncogenic: The variants L858R and L861X are described as actionable mutations within the context of EGFR, suggesting their role in tumor development or progression.

Gene→Variant (gene-first): 1956:L858R 1956:L861X

Genes: 1956

Variants: L858R L861X

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 27

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the impact of the insertions on the catalytic Gln61 might be stronger, indicating an alteration in molecular function related to GTP hydrolysis.

Gene→Variant (gene-first): 5921:Gln61

Genes: 5921

Variants: Gln61

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 25

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the HRAS p.G12V variant alters the signaling capability by affecting GTP hydrolysis and inducing phosphorylation of ERK and AKT, indicating a change in molecular function. Oncogenic: The HRAS p.G12V variant is implicated in inducing signaling pathways that are associated with tumor development, as evidenced by the increased levels of phosphorylated ERK and AKT in the transfected cells.

Gene→Variant (gene-first): 3845:p.G12V

Genes: 3845

Variants: p.G12V

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 22

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the classical oncogenic variant KRAS p.G12V in the context of its effect on GTP hydrolysis, indicating its role in tumor development or progression. Functional: The passage describes how the variant KRAS p.G12V affects the biochemical function of GTP hydrolysis, demonstrating its impact on molecular activity in the presence of RAS-GAP.

Gene→Variant (gene-first): 3845:p.G12V

Genes: 3845

Variants: p.G12V

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 21

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.G12V variant alters the intrinsic GTP hydrolysis rates, indicating a change in molecular function related to protein activity. Oncogenic: The p.G12V variant is described as a classical oncogenic variant, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 3845:p.G12V

Genes: 3845

Variants: p.G12V

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 18

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: KRAS p.G12V is described as a classical oncogenic variant, indicating its contribution to tumor development or progression. Functional: The passage discusses how KRAS p.G12V alters the intrinsic dissociation rate of mGppNHp compared to wild type, indicating a change in molecular function.

Gene→Variant (gene-first): 3845:p.G12V

Genes: 3845

Variants: p.G12V

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the impact of the p.Q61L variant on nucleotide exchange, effector binding, and GTP hydrolysis, indicating that it alters molecular or biochemical function. Oncogenic: The p.Q61L variant is described as a classic pathogenic missense mutation, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 4893:p.Q61L

Genes: 4893

Variants: p.Q61L

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the insertions around Gln61 likely alter the molecular interactions and functions of the protein, particularly affecting GTP hydrolysis and interactions with GEFs and GAPs.

Gene→Variant (gene-first): 5921:Gln61

Genes: 5921

Variants: Gln61

[Paragraph-level] PMCID: PMC6547725 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses mutations in RAS genes, including p.G12A, p.G13H, and p.Q22K, which are described as classical oncogenic mutations that affect tumor development and progression. Functional: The passage indicates that the p.Q22K mutation is associated with increased GTP loading, suggesting that it alters molecular function related to protein activity.

Gene→Variant (gene-first): 3845:p.G12A 3845:p.G13H 3845:p.Q22K

Genes: 3845

Variants: p.G12A p.G13H p.Q22K

[Paragraph-level] PMCID: PMC3058384 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The B-RAFV600E mutation predicts a dependency on the MAPK signaling cascade in melanoma, and this is validated by the success of RAF and MEK inhibitors in clinical trials, indicating a correlation with treatment response. Oncogenic: The passage discusses oncogenic mutations in B-RAF, specifically the B-RAFV600E mutation, which is implicated in tumor development and progression in malignant melanomas.

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

Genes: 673

Variants: B-RAFV600E serine/threonine

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how several variants, including K131, R168G, G130R, and others, alter the molecular function of RAD51C by disrupting the ATP-binding site and influencing RAD51C activity, as demonstrated in HDR assays. Oncogenic: The passage indicates that the variants are deleterious and influence RAD51C function, which is relevant to tumor development or progression, particularly in the context of HDR assays.

Gene→Variant (gene-first): 5889:16 A 5889:C135Y 5889:E94K 5889:G130R 5889:G302V 5889:K131 5889:L138F 5889:P21S 5889:Q133E 5889:R168 5889:R168G 5889:R312 5889:R312W 5889:T132I 5889:T132R 5892:T86I 5889:V140E 5889:p.Cys135Tyr 5889:p.Thr132Ile 5889:p.Val140Glu

Genes: 5889 5892

Variants: 16 A C135Y E94K G130R G302V K131 L138F P21S Q133E R168 R168G R312 R312W T132I T132R T86I V140E p.Cys135Tyr p.Thr132Ile p.Val140Glu

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how various RAD51C variants affect the ability to form protein complexes involved in DNA damage repair, indicating that these variants alter molecular function. Oncogenic: The mention of deleterious variants that lose the ability to form complexes suggests a role in tumor development or progression, as these variants are associated with impaired DNA repair mechanisms.

Gene→Variant (gene-first): 5889:A126T 5889:D109Y 5889:D159N 5889:G162E 5889:G302V 5889:L138F 5889:L27P 5889:Q133E 5889:R258H 5889:S163R 5889:T336P 5892:T86I 5889:p.Gly162Glu 5889:p.Ser163Arg 5889:p.Thr336Pro 5892:p.Thr86Ile

Genes: 5889 5892

Variants: A126T D109Y D159N G162E G302V L138F L27P Q133E R258H S163R T336P T86I p.Gly162Glu p.Ser163Arg p.Thr336Pro p.Thr86Ile

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how RAD51C variants alter cell proliferation and the formation of RAD51 foci in response to ionizing radiation, indicating changes in molecular function related to DNA damage signaling and repair. Oncogenic: The variants are implicated in a proliferation defect and disruption of homologous recombination (HR) repair, suggesting their role in tumor development or progression.

Gene→Variant (gene-first): 5889:G130R 5889:G302V 5889:K131I 5889:L138F 5889:Q133E 5889:R168G 5889:T132R

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how the L138F variant alters HDR activity in different cell lines, indicating a change in molecular function. Predictive: The passage mentions the sensitivity of variants, including L138F, to cisplatin and olaparib, suggesting a correlation with response to these therapies.

Gene→Variant (gene-first): 5889:L138F

Genes: 5889

Variants: L138F

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the sensitivity of specific RAD51C variants (G130R, K131I, T132R, Q133E, and G302V) to olaparib, indicating a correlation with response to therapy. Functional: The passage describes the introduction of RAD51C variants into a cell line and assesses their effects on homologous recombination repair (HDR), indicating that these variants alter molecular function.

Gene→Variant (gene-first): 5889:G130R 5889:G302V 5889:K131I 5889:L138F 5889:Q133E 5889:R168G 5889:T132R

Genes: 5889

Variants: G130R G302V K131I L138F Q133E R168G T132R

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how RAD51C missense variants alter RAD51 foci formation in response to DNA damage, indicating a change in molecular function related to DNA repair mechanisms. Predictive: The mention of "drug response findings" suggests that the variants may correlate with sensitivity or resistance to a specific therapy, indicating predictive evidence.

Gene→Variant (gene-first): 5889:A155E 5889:C135Y 5889:C147Y 5888:D108G 5889:D109Y 5889:D159Y 5889:G306R 5889:P21S 5889:V140E 5889:p.Ala155Glu 5888:p.Asp108Gly 5889:p.Asp109Tyr 5889:p.Asp159Tyr 5889:p.Cys147Tyr 5889:p.Gly306Arg 5889:p.Pro21Ser 5889:p.Val140Glu

Genes: 5889 5888

Variants: A155E C135Y C147Y D108G D109Y D159Y G306R P21S V140E p.Ala155Glu p.Asp108Gly p.Asp109Tyr p.Asp159Tyr p.Cys147Tyr p.Gly306Arg p.Pro21Ser p.Val140Glu

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 5

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the influence of RAD51C missense variants on the response to cisplatin and olaparib, indicating a correlation between the variants and treatment sensitivity. Functional: The passage describes how the variants affect IC50 values in the HDR assay, suggesting that they alter molecular function related to drug response.

Gene→Variant (gene-first): 5889:E94K 5889:G306R 5889:p.Glu94Lys 5889:p.Gly306Arg

Genes: 5889

Variants: E94K G306R p.Glu94Lys p.Gly306Arg

[Paragraph-level] PMCID: PMC10390864 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the influence of missense mutations on RAD51C HR DNA repair activity, indicating that the variants alter molecular function as assessed by HDR activity in a cell-based assay. Oncogenic: The mention of deleterious variants categorized based on their impact on HDR activity suggests that these somatic variants contribute to tumor development or progression through their effects on DNA repair mechanisms.

Gene→Variant (gene-first): 5889:A126T 5889:C135Y 5889:D159N 5889:G125V 5889:G153D 5889:G264S 5889:G264V 5889:G3R 5889:L138F 5889:L219S 5889:Q143R 5889:R214C 5889:R258H 5889:R312W 5889:R366Q 5889:T287A 5889:V169A 5889:p.Arg214Cys 5889:p.Arg258His 5889:p.Arg312Trp 5889:p.Arg366Gln 5889:p.Asp159Asn 5889:p.Gln143Arg 5889:p.Gly125Val 5889:p.Gly153Asp 5889:p.Gly264Ser 5889:p.Gly264Val 5889:p.Gly3Arg 5889:p.Leu219Ser 5889:p.Thr287Ala 5889:p.Val169Ala

Genes: 5889

Variants: A126T C135Y D159N G125V G153D G264S G264V G3R L138F L219S Q143R R214C R258H R312W R366Q T287A V169A p.Arg214Cys p.Arg258His p.Arg312Trp p.Arg366Gln p.Asp159Asn p.Gln143Arg p.Gly125Val p.Gly153Asp p.Gly264Ser p.Gly264Val p.Gly3Arg p.Leu219Ser p.Thr287Ala p.Val169Ala

[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the treatment of ruxolitinib and its effects on the phosphorylation level of STAT3 in tumors with the JAK1 S703I mutation, indicating a correlation with treatment response. Oncogenic: The mention of the JAK1 S703I mutation in the context of tumor models suggests that this somatic variant contributes to tumor development or progression.

Gene→Variant (gene-first): 3716:S703I

Genes: 3716

Variants: S703I

[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of the JAK1S703I mutation to the JAK1/2 inhibitor ruxolitinib, indicating a correlation with treatment response. Oncogenic: The passage suggests that the JAK1S703I mutation may play a critical role in tumorigenesis, indicating its contribution to tumor development.

Gene→Variant (gene-first): 3716:S703I

Genes: 3716

Variants: S703I

[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 10

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the anti-tumor activity of ruxolitinib in a model with the JAK1 S703I mutation, indicating a correlation with response to therapy. Oncogenic: The mention of the JAK1 S703I mutation in the context of a PDX model suggests that this somatic variant contributes to tumor development or progression.

Gene→Variant (gene-first): 3716:S703I

Genes: 3716

Variants: S703I

[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the transformation ability of JAK1 mutations, specifically noting that JAK1S703I and JAK1S729C are capable of continual proliferation in the absence of IL-3, indicating their contribution to tumor development or progression. Functional: The passage mentions that JAK1S703I activates the JAK-STAT signaling pathway, which indicates an alteration in molecular function related to the variant.

Gene→Variant (gene-first): 3716:E483D 3716:S703I 3716:S729C

Genes: 3716

Variants: E483D S703I S729C

[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the introduction of JAK1 mutations, including E483D, S703I, and S729C, alters the expression levels of phosphorylated JAK1 and STAT proteins, indicating a change in molecular function. Oncogenic: The passage mentions that JAK1S729C is a known and recurrent activating mutation, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 3716:E483D 3716:S703I 3716:S729C

Genes: 3716

Variants: E483D S703I S729C

[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage indicates that the S703I mutation is an activating mutation of the JAK1 gene and was found in tumors, suggesting it contributes to tumor development or progression. Functional: The S703I mutation is described as potentially causing disruption of auto-inhibition of the JAK1 kinase, indicating an alteration in molecular or biochemical function.

Gene→Variant (gene-first): 3716:A1086S 3716:E483D 728378:N451S 3716:S703I

Genes: 3716 728378

Variants: A1086S E483D N451S S703I

[Paragraph-level] PMCID: PMC4868698 Section: RESULTS PassageIndex: 3

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 3716:A1086S 3716:E483D 728378:N451S 3716:S703I

Genes: 3716 728378

Variants: A1086S E483D N451S S703I

[Paragraph-level] PMCID: PMC7472556 Section: RESULTS PassageIndex: 23

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses how NRG1 levels increase after androgen deprivation therapy (ADT) and suggests that these elevated levels are sufficient to promote resistance to ADT, indicating a correlation with treatment response. Oncogenic: The mention of NRG1 promoting resistance to ADT implies a role in tumor development or progression, which aligns with the definition of an oncogenic variant.

Gene→Variant (gene-first): 8850:S7C

Genes: 8850

Variants: S7C

[Paragraph-level] PMCID: PMC7472556 Section: RESULTS PassageIndex: 21

Evidence Type(s): Diagnostic, Predictive

Justification: Diagnostic: The passage discusses the detection of NRG1 expression in patients with localized prostate cancer, indicating its potential role in classifying or defining the disease based on the presence or absence of NRG1 staining. Predictive: The analysis includes a comparison of NRG1 expression in patients who received neoadjuvant ADT versus those who were hormonally intact, suggesting a correlation with treatment response.

Gene→Variant (gene-first): 3084:S6 8850:S7

Genes: 3084 8850

Variants: S6 S7

[Paragraph-level] PMCID: PMC7472556 Section: RESULTS PassageIndex: 19

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 1956:S2 3084:S6C

Genes: 1956 3084

Variants: S2 S6C

[Paragraph-level] PMCID: PMC7472556 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses resistance-promoting activity and its correlation with HER3 phosphorylation, indicating a relationship with response or resistance to therapy. Functional: The passage describes how the variant affects HER3 phosphorylation activity, suggesting an alteration in molecular function related to resistance-promoting activity.

Gene→Variant (gene-first): 5979:Q8

Genes: 5979

Variants: Q8

[Paragraph-level] PMCID: PMC4899144 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the somatic mutations Y641F and Y646F in the EZH2 gene contribute to tumor development, specifically leading to high-penetrance lymphoma and melanoma in a mouse model. Functional: The variant Ezh2Y641F is shown to alter molecular function by increasing global H3K27 trimethylation and causing a redistribution of this mark, which affects transcription at various loci.

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

Genes: 2146

Variants: Y641F Y646F

[Paragraph-level] PMCID: PMC5029699 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the impact of FGFR3 kinase domain variants on drug responses and highlights the distinct changes in efficacy of inhibitors based on specific activating mutations, indicating a correlation with treatment response. Oncogenic: The mention of FGFR3 variants as drivers in diverse tumors suggests that these somatic mutations contribute to tumor development or progression.

Gene→Variant (gene-first): 2261:K650E 2261:N540K 2261:R669G

Genes: 2261

Variants: K650E N540K R669G

[Paragraph-level] PMCID: PMC4378307 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage indicates that KRAS mutation, specifically G12D, is associated with a poor prognosis in progression-free survival (PFS), demonstrating its role as an independent negative prognostic factor. Diagnostic: The mention of KRAS mutations, including G12D, being associated with specific outcomes in patients suggests that these mutations can be used to classify or define disease subtypes.

Gene→Variant (gene-first): 3845:G12D

Genes: 3845

Variants: G12D

[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 20

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

Justification: Diagnostic: The passage discusses the frequencies of MAP2K1 variants in CRC patients and their association with specific tumor characteristics, indicating their role in defining or classifying the disease. Prognostic: The variants are correlated with worse disease/progression-free survival, suggesting they have prognostic implications independent of therapy. Predictive: The passage mentions that MAP2K1 mutations are associated with de novo and acquired resistance to anti-EGFR MoAbs, indicating a predictive relationship with therapy response. Oncogenic: The variants are described as contributing to a gain of function of the MEK1 protein, which is indicative of their role in tumor development or progression.

Gene→Variant (gene-first): 5604:c.169A>G 5604:c.199G>A 5604:p.Asp67Asn 5604:p.Lys57Glu

Genes: 5604

Variants: c.169A>G c.199G>A p.Asp67Asn p.Lys57Glu

[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 16

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses the response of patients to cetuximab-based first-line therapy, specifically noting that patient P4, who carries the FBXW7 variant c.1268G>T; p.Gly423Val, had a complete response to this therapy. Diagnostic: The mention of the FBXW7 variant in the context of patient P4's treatment response suggests that it may be used to classify or define the patient's disease or treatment outcome.

Gene→Variant (gene-first): 55294:c.1268G>T 55294:p.Gly423Val

Genes: 55294

Variants: c.1268G>T p.Gly423Val

[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 14

Evidence Type(s): Prognostic, Oncogenic

Justification: Prognostic: The passage indicates that two missense mutations are associated with patients having a shorter progression-free survival (PFS), suggesting a correlation with disease outcome. Oncogenic: The FBXW7 p.Arg505Cys mutation is reported to lead to loss of function of the protein and has been associated with several cancer types, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): 55294:c.1513C>T 1956:c.1798G>A 55294:p.Arg505Cys 673:p.Asp600Asn

Genes: 55294 1956 673

Variants: c.1513C>T c.1798G>A p.Arg505Cys p.Asp600Asn

[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 13

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The variants in NF1 are described as contributing to tumor development by leading to a loss of function and increased activation of the RAS signaling pathway, indicating their role in oncogenesis. Prognostic: The passage provides progression-free survival (PFS) times for the patients with the variants, suggesting a correlation between the variants and disease outcome.

Gene→Variant (gene-first): 4763:c.5101A>T 4763:c.638_639insA 4763:p.Asn214Lys fs*2 4763:p.Lys1701Ter

Genes: 4763

Variants: c.5101A>T c.638_639insA p.Asn214Lys fs*2 p.Lys1701Ter

[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The variant c.169A>G results in an amino acid substitution (p.Lys57Glu) that is associated with a gain of function of the MEK1 protein, indicating an alteration in molecular function. Oncogenic: The variant is discussed in the context of its role in the MAP2K1 gene, which is known to contribute to tumor development or progression, suggesting its oncogenic potential.

Gene→Variant (gene-first): 5604:c.169A>G 5604:p.Lys57Glu

Genes: 5604

Variants: c.169A>G p.Lys57Glu

[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the KRAS variant (c.183A>T; p.Gln61His) identified in tumor tissue, indicating its role in tumor development or progression as it is associated with a specific patient's tumor.

Gene→Variant (gene-first): 3845:c.183A>T 3845:p.Gln61His

Genes: 3845

Variants: c.183A>T p.Gln61His

[Paragraph-level] PMCID: PMC6627713 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of specific variants in patients and their association with APC and TP53 mutations, indicating their role in defining or classifying the disease context. Oncogenic: The variants mentioned are associated with tumors, suggesting that they contribute to tumor development or progression, which aligns with the definition of oncogenic variants.

Gene→Variant (gene-first): 7157:c.275_276insGGCC 324:c.4098_4099delTCinsAT 324:c.4467_4468insCATTTTG 324:c.589_590insGAGTT 324:c.837_838InsG

Genes: 7157 324

Variants: c.275_276insGGCC c.4098_4099delTCinsAT c.4467_4468insCATTTTG c.589_590insGAGTT c.837_838InsG

[Paragraph-level] PMCID: PMC10283448 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses mutations identified in patients who progressed on repotrectinib treatment, suggesting a potential role of these variants in acquired resistance to the therapy. Functional: The passage indicates that further studies are necessary to investigate the functional role of the mutations, implying that these variants may alter molecular or biochemical functions related to resistance mechanisms.

Gene→Variant (gene-first): 1050:196_197insHP 7157:E171G 896:E253Q 2064:H178Q 7157:H179Y 5925:H555R 2064:R143Q

Genes: 1050 7157 896 2064 5925

Variants: 196_197insHP E171G E253Q H178Q H179Y H555R R143Q

[Paragraph-level] PMCID: PMC10283448 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses the clinical activity of repotrectinib in a patient with the G2032R mutation, indicating a response to therapy, which aligns with predictive evidence. Diagnostic: The G2032R mutation is identified in the context of a ROS1-rearranged patient, suggesting its role in defining the patient's disease subtype.

Gene→Variant (gene-first): 6098:G2032R

Genes: 6098

Variants: G2032R

[Paragraph-level] PMCID: PMC10283448 Section: RESULTS PassageIndex: 10

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the response of the ROS1-G2032R mutation to various therapies, specifically mentioning the effectiveness of cabozantinib and repotrectinib in inhibiting growth, which correlates with treatment response. Oncogenic: The ROS1-G2032R mutation is implicated in tumor growth, as indicated by the investigation of its effects in Ba/F3 cells and the context of progression on crizotinib treatment, suggesting its role in tumor development.

Gene→Variant (gene-first): 6098:G2032R

Genes: 6098

Variants: G2032R

[Paragraph-level] PMCID: PMC10283448 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive

Justification: Predictive: The passage indicates that repotrectinib is effective against crizotinib-resistant ROS1 G2032R, suggesting a correlation between the variant and response to therapy.

Gene→Variant (gene-first): 6098:G2032R

Genes: 6098

Variants: G2032R

[Paragraph-level] PMCID: PMC3260002 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the detection of DNMT3A exon 23 mutations in AML patients, indicating that these mutations are associated with the disease, which supports their use in defining or confirming the disease. Oncogenic: The mention of DNMT3A mutations in AML patients suggests that these somatic variants contribute to tumor development or progression, as they are identified in a cancer context.

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

Genes: 1788

Variants: R882 R882C R882H R882P W893 W893S

[Paragraph-level] PMCID: PMC4695055 Section: RESULTS PassageIndex: 5

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 1956:T790M 673:V600E

Genes: 1956 673

Variants: T790M V600E

[Paragraph-level] PMCID: PMC4695055 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage indicates that the variant c.3082+811A TTTTAACA > GGTTTGAT is found in all GI cancer samples, suggesting its association with the disease. Oncogenic: The presence of the variant in GI cancer samples implies a potential role in tumor development or progression, as it is discussed in the context of mutations in cancer.

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

Genes: 7157

Variants: c.3082+811A TTTTAACA > GGTTTGAT

[Paragraph-level] PMCID: PMC4695055 Section: RESULTS PassageIndex: 2

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 4916:p.982_1028del47

Genes: 4916

Variants: p.982_1028del47

[Paragraph-level] PMCID: PMC4884999 Section: RESULTS PassageIndex: 3

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the frequency of KRAS mutations, specifically mentioning that the majority occur in codon 12 with G12C being the most common, indicating its association with lung cancer subtypes. Oncogenic: The mention of KRAS mutations, including G12C, in the context of lung adenocarcinoma suggests that this somatic variant contributes to tumor development or progression.

Gene→Variant (gene-first): 3845:G12C

Genes: 3845

Variants: G12C

[Paragraph-level] PMCID: PMC7568619 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The variant L1196Q is associated with the development of resistance to ALK inhibitors, and its identification guided the prescription of a newer ALK inhibitor, ceritinib, which resulted in a partial response in the patient. Oncogenic: The passage indicates that the L1196Q mutation is a secondary mutation that developed in the context of drug resistance, suggesting it contributes to tumor progression and the development of resistance to therapy.

Gene→Variant (gene-first): 238:L1196Q

Genes: 238

Variants: L1196Q

[Paragraph-level] PMCID: PMC3422615 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Diagnostic, Prognostic, Oncogenic

Justification: Diagnostic: K27M-H3.3 mutation defines clinically and biologically distinct subgroups in DIPG, indicating its use in classifying the disease. Prognostic: K27M-H3.3 is universally associated with short survival in DIPG, while patients wild-type for H3.3 show improved survival, indicating its correlation with disease outcome. Oncogenic: The K27M-H3.3 mutation contributes to tumor development or progression in pediatric glioblastomas, as indicated by its prevalence in DIPG and association with specific copy number changes.

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

Genes: 3021

Variants: G34V G34V/R K27M

[Paragraph-level] PMCID: PMC3100313 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses heterozygous somatic mutations in IDH1, specifically the R132H variant, and its association with tumorigenesis in gliomas, indicating that this variant contributes to tumor development or progression. Functional: The passage mentions that mutations in IDH1, including R132H, cause loss of normal enzyme function and gain-of-function, leading to the accumulation of D-2-hydroxyglutarate, which alters the biochemical function of the enzyme.

Gene→Variant (gene-first): 3417:R132H

Genes: 3417

Variants: R132H

[Paragraph-level] PMCID: PMC3100313 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the frequency of heterozygous mutations of IDH1, specifically the c.395G>A variant, in glioblastomas, indicating its association with this disease subtype. Oncogenic: The presence of the IDH1 mutation (p.R132H) in glioblastomas suggests that this somatic variant contributes to tumor development or progression.

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

Genes: 728294 79944 3417

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

[Paragraph-level] PMCID: PMC4823825 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Diagnostic

Justification: Oncogenic: The passage discusses how the K27M mutation contributes to tumorigenesis in DIPGs, indicating its role in tumor development and progression. Diagnostic: The K27M mutation is associated with the diagnosis of DIPGs, as it helps guide diagnosis and targeted therapies in these tumors.

Gene→Variant (gene-first): 8358:K27M

Genes: 8358

Variants: K27M

[Paragraph-level] PMCID: PMC2570525 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Diagnostic, Oncogenic, Functional

Justification: Diagnostic: The passage discusses the identification of the AKT1 (E17K) mutation in various cancer types, indicating its association with melanoma and suggesting its role in defining the presence of this mutation in cancer specimens. Oncogenic: The passage states that the AKT1 E17K mutation is an activating mutation that contributes to tumor development, as evidenced by its identification in melanoma specimens and cell lines, indicating its role in cancer progression. Functional: The passage mentions that the AKT3 E17K mutation results in the activation of AKT when expressed in human melanoma cells, demonstrating a change in molecular function related to the variant.

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

Genes: 207

Variants: AKT1 (E17K E17K

[Paragraph-level] PMCID: PMC10161095 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the lysine-to-methionine mutation at lysine 27 (H3K27M) contributes to tumor development and progression in diffuse midline gliomas, indicating its role as a somatic variant in cancer. Functional: The variant alters molecular function by affecting the levels of proteins in the SWI/SNF complex and influencing chromatin modifications, demonstrating its impact on biochemical processes within the tumor cells.

Gene→Variant (gene-first): 3021:lysine 27 55193:lysine-to-methionine

Genes: 3021 55193

Variants: lysine 27 lysine-to-methionine

It is fantastic that they were using the listed learning strategies, but were they using them effectively? From experience, I believe that transitions are among the hardest things to implement in education. Perhaps it was a product of throwing a bunch of ideas against the wall and seeing what sticks? Without the educator himself reflecting, only the students know the quality of the education they received.

[Paragraph-level] PMCID: PMC9859631 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses various mutations, including Y1230H, D1288N L1195I, and L1195V, which are described as secondary mutations associated with MET TKI resistance, indicating a correlation with treatment response. Oncogenic: The mention of mutations contributing to resistance against targeted therapies suggests that these variants may play a role in tumor development or progression, particularly in the context of lung cancer.

Gene→Variant (gene-first): 79811:D1288N L1195I 79811:L1195V 79811:Y1230H 2064:c.1899-936_1946+520del

Genes: 79811 2064

Variants: D1288N L1195I L1195V Y1230H c.1899-936_1946+520del

[Paragraph-level] PMCID: PMC9859631 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the presence of the EGFR L858R variant in a patient with advanced LUAD and its association with resistance to osimertinib, indicating a correlation with treatment response. Oncogenic: The mention of the EGFR L858R variant and its role in the context of advanced LUAD suggests that it contributes to tumor development or progression, particularly as it is associated with resistance mechanisms.

Gene→Variant (gene-first): 2064:D769Y 2064:L755S 1956:L858R 2064:c.1899-32_1909del

Genes: 2064 1956

Variants: D769Y L755S L858R c.1899-32_1909del

[Paragraph-level] PMCID: PMC9859631 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Predictive

Justification: Diagnostic: The passage discusses the detection of ERBB2 variants in patients, indicating their association with specific cases, which supports their use in defining or classifying a disease subtype. Predictive: The mention of the novel variant ERBB2 c.1899-2A>G being detected after treatment suggests a potential correlation with treatment response, indicating its relevance in predicting therapy outcomes.

Gene→Variant (gene-first): 2064:c.1899-2A>G 2064:c.1899-880_1946+761del

Genes: 2064

Variants: c.1899-2A>G c.1899-880_1946+761del

[Paragraph-level] PMCID: PMC5111006 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage indicates that the homozygous CHEK2 variant p.R474C was contributory to familial cancer, and the inactivation of CHEK2 in mice led to cancers in multiple organs, suggesting a role in tumor development. Functional: The variant p.R474C alters the tertiary structure of the CHK2 protein by disrupting a salt bridge, and subsequent analysis showed that it was unstable and scarcely activated, indicating a change in molecular function.

Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C

Genes: 11200

Variants: p.R474 p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 18

Evidence Type(s): Diagnostic, Predisposing

Justification: Diagnostic: The passage states that the variants are recorded as disease-associated variants, indicating their use in defining or classifying diseases such as diabetes, carotid intima media thickness, and oligospermia. Predisposing: The variants mentioned are associated with inherited conditions, suggesting they confer an inherited risk for developing diseases, although the germline nature is implied rather than explicitly stated.

Gene→Variant (gene-first): 440822:rs11703684 6289:rs2468844 3767:rs5215 3767:rs5219 6833:rs757110

Genes: 440822 6289 3767 6833

Variants: rs11703684 rs2468844 rs5215 rs5219 rs757110

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 17

Evidence Type(s): Predisposing, Diagnostic

Justification: Predisposing: The passage discusses variants in hereditary loci, specifically mentioning TP53 and BRCA2, which are associated with inherited cancer syndromes, indicating a potential inherited risk for developing disease. Diagnostic: The passage mentions the classification of variants as "Benign" or of "Uncertain significance," which relates to their use in defining or classifying disease risk or status.

Gene→Variant (gene-first): 7157:p.P72R 675:p.V2466A 7157:rs1042522 2956:rs1042821 4072:rs1126497 675:rs169547 5395:rs1805323 5395:rs2228006 4436:rs2303424

Genes: 7157 675 2956 4072 5395 4436

Variants: p.P72R p.V2466A rs1042522 rs1042821 rs1126497 rs169547 rs1805323 rs2228006 rs2303424

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.R474C variant alters the molecular function of the CHK2 protein, demonstrating that it is poorly expressed and activated by DNA damage compared to the wild-type protein. Oncogenic: The context implies that the p.R474C variant contributes to tumor development or progression by affecting the function of a cell cycle checkpoint regulator, which is critical in the context of cancer biology.

Gene→Variant (gene-first): 11200:p.R474C

Genes: 11200

Variants: p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Justification: Functional: The passage indicates that the p.R474C variant affects the activation of the CHK2 protein in response to DNA damage, suggesting an alteration in its molecular function.

Gene→Variant (gene-first): 11200:p.R474C

Genes: 11200

Variants: p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant p.R210 and its substitution p.R210Q relate to the structure and potential function of the protein, indicating that p.R210Q is not likely to affect the function and structure of the protein.

Gene→Variant (gene-first): 2217:p.R210 2217:p.R210Q

Genes: 2217

Variants: p.R210 p.R210Q

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant p.R474C alters the salt bridge formation and is likely to make the protein unstable, indicating an alteration in molecular function. Oncogenic: The variant p.R474C is described as "disease causing" and likely interferes with protein function, suggesting a role in tumor development or progression.

Gene→Variant (gene-first): 11200:p.R474 11200:p.R474C

Genes: 11200

Variants: p.R474 p.R474C

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variant p.R474 in CHEK2 was analyzed for its effect on protein function based on evolutionary conservation, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 11200:p.R474

Genes: 11200

Variants: p.R474

[Paragraph-level] PMCID: PMC5111006 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the presence of the L858R mutation in the context of lung cancer, indicating its potential role in tumor development or progression.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC6333965 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage mentions that PIK3CA E545K and CDKN2A R58X are potentially targetable alterations, indicating their association with specific tumor characteristics or responses, which aligns with diagnostic evidence. Oncogenic: The variants PIK3CA E545K and CDKN2A R58X are described as potentially targetable alterations, suggesting their role in tumor development or progression, which supports oncogenic evidence.

Gene→Variant (gene-first): 5290:E545K 1029:R58X

Genes: 5290 1029

Variants: E545K R58X

[Paragraph-level] PMCID: PMC5509015 Section: RESULTS PassageIndex: 14

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the frequency and types of mutations observed in human ccRCC, indicating that these mutations are associated with the disease, thus providing evidence for their role in defining or classifying the disease. Oncogenic: The passage describes mutations in primary cilium-related genes that contribute to the formation of ccRCC precursor lesions in mice, indicating that these somatic variants play a role in tumor development.

Gene→Variant (gene-first): 7428:A>G 7428:C>A 7428:C>T 7428:G>A 7428:G>T 7428:T>C

Genes: 7428

Variants: A>G C>A C>T G>A G>T T>C

[Paragraph-level] PMCID: PMC5509015 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the deletion of Trp53 in mice and its contribution to tumor development, as evidenced by the increased incidence and earlier onset of tumors in VhlDelta/DeltaTrp53Delta/DeltaRb1Delta/Delta mice compared to other genotypes. Functional: The deletion of Trp53 is described in the context of its role in the p53/G1-S network, indicating that it alters the molecular function related to cell cycle control and tumorigenesis.

Gene→Variant (gene-first): 7428:Trp53 deletion

Genes: 7428

Variants: Trp53 deletion

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 15

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity of cells expressing K-RasG12D to specific therapies, indicating a correlation between the variant and response to treatment with MEK and PI3K inhibitors. Oncogenic: The mention of K-RasG12D in the context of transformed Ba/F3 cells suggests that this somatic variant contributes to tumor development or progression, as it is involved in cytokine-independent growth.

Gene→Variant (gene-first): 3845:K-RasG12D

Genes: 3845

Variants: K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the ability of mutant K-Ras proteins to bind to effectors in vitro, indicating that the variants alter molecular interactions, specifically the binding to FLAG-p110alpha. Oncogenic: The mention of K-RasG12D and the other mutant variants in the context of their binding interactions suggests that these somatic variants contribute to tumor development or progression through their altered functional properties.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D 5290:Y64G

Genes: 5295 3845 5290

Variants: A66dup K-RasG12D Y64G

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K-RasG12D variant alters the levels of pERK and pAkt, indicating a change in molecular function related to signaling pathways. Oncogenic: The K-RasG12D variant is implicated in modulating effector pathway activation, which suggests its role in tumor development or progression.

Gene→Variant (gene-first): 3845:K-RasG12D

Genes: 3845

Variants: K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes how the K-RasG12D variant and tandem duplication mutants transform Ba/F3 cells to cytokine-independent growth, indicating their role in tumor development or progression. Functional: The passage mentions that Ba/F3 cells expressing K-RasG12D and the tandem duplication mutants had elevated levels of Ras-GTP, suggesting that these variants alter molecular function related to Ras signaling.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants K-RasG60_A66dup and K-RasE62_A66dup alter the biochemical properties of K-Ras, specifically their GTPase activity and response to GAP stimulation, indicating a change in molecular function. Oncogenic: The variants are described in the context of their role in accumulating in the active GTP conformation and exhibiting impaired GTPase activity, which suggests their contribution to tumor development or progression.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant Glutamine 61 (Q61) may alter protein-protein interactions and the structural dynamics of Ras, indicating a change in molecular function due to the predicted effects of switch 2 insertions. Oncogenic: The analysis suggests that the alterations in the Ras protein structure, particularly involving Q61, may contribute to the GTP conformation of Ras, which is associated with tumor development and progression.

Gene→Variant (gene-first): 3845:Glutamine 61 3845:Q61

Genes: 3845

Variants: Glutamine 61 Q61

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 5

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses how the K-RasG12D variant induces cytokine-independent colony formation and contributes to abnormal growth patterns in hematopoietic progenitor cells, indicating its role in tumor development. Functional: The variant K-RasG12D alters the growth response of progenitor cells to GM-CSF, demonstrating a change in molecular function related to colony formation.

Gene→Variant (gene-first): 5295:A66dup 3845:K-RasG12D

Genes: 5295 3845

Variants: A66dup K-RasG12D

[Paragraph-level] PMCID: PMC4748120 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage describes a partial duplication of the K-Ras gene that is associated with juvenile myelomonocytic leukaemia (JMML), indicating that the variant contributes to tumor development or progression. Functional: The immunoblot analysis shows that the variant alters the molecular function of K-Ras, as evidenced by the detection of a band with reduced electrophoretic mobility compared to normal Ras protein, indicating a change in protein behavior.

Gene→Variant (gene-first): 3845:c.178_198dup 3845:c.184_198dup

Genes: 3845

Variants: c.178_198dup c.184_198dup

[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the effects of combination therapies on cell proliferation in osimertinib-resistant cell lines, indicating a relationship between the presence of the T790M mutation and the response to therapy, specifically mentioning osimertinib and naquotinib. Oncogenic: The T790M mutation is maintained in the osimertinib-resistant RPC-9/OsiR cells, suggesting its role in tumor development or progression, particularly in the context of resistance to therapy.

Gene→Variant (gene-first): 1956:C797S 1956:T790M

Genes: 1956

Variants: C797S T790M

[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 10

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses gefitinib-resistant lung adenocarcinoma cell lines harboring the EGFR exon 19del and T790M mutations, indicating a correlation with resistance to therapy, specifically gefitinib. Oncogenic: The mention of the EGFR exon 19del and T790M mutations in the context of gefitinib resistance suggests that these somatic variants contribute to tumor development or progression in lung adenocarcinoma.

Gene→Variant (gene-first): 1956:19del 1956:T790M

Genes: 1956

Variants: 19del T790M

[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 8

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The passage discusses the role of the EGFR exon 19del variant in the development of a resistant cell line, indicating that this somatic variant contributes to tumor progression and resistance mechanisms in lung cancer cells. Predictive: The passage mentions that the combination of EGFR-TKIs and MET inhibitors showed an excellent inhibitory effect on cell proliferation in the resistant cell line, suggesting a correlation between the variant and response to therapy.

Gene→Variant (gene-first): 1956:19del

Genes: 1956

Variants: 19del

[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 4

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the acquired EGFR C797S mutation in the context of resistance to osimertinib, indicating that this variant correlates with resistance to a specific therapy. Oncogenic: The C797S mutation is described as contributing to resistance in cell lines, suggesting its role in tumor progression or development in the context of EGFR-TKI treatment.

Gene→Variant (gene-first): 1956:C797S

Genes: 1956

Variants: C797S

[Paragraph-level] PMCID: PMC5792548 Section: RESULTS PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the establishment of naquotinib-resistant lung cancer cells and mentions the effectiveness of naquotinib in inhibiting cell proliferation, indicating a correlation between the variants (19del and T790M) and resistance to therapy. Oncogenic: The presence of the T790M mutation in acquired gefitinib-resistant cells suggests that it contributes to tumor development or progression, as it is associated with resistance mechanisms in lung cancer.

Gene→Variant (gene-first): 1956:19del 1956:T790M

Genes: 1956

Variants: 19del T790M

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 22

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the correlation between the FGFR3 S249C variant and the response to treatment with FGFR TKIs, indicating that patients with this mutation exhibited partial or complete responses, which aligns with predictive evidence. Oncogenic: The FGFR3 S249C variant is described as the most frequent mutation of FGFR3, suggesting its role in tumor development or progression, which supports its classification as oncogenic.

Gene→Variant (gene-first): 2261:S249C

Genes: 2261

Variants: S249C

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 21

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the mutations E545K, E542K, and H1047R are described as "oncogenic mutations," suggesting they contribute to tumor development or progression.

Gene→Variant (gene-first): 5290:E542K 5290:E545K 5290:H1047R

Genes: 5290

Variants: E542K E545K H1047R

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 20

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The passage discusses the transforming activities of FGFR3 S249C compound mutations, indicating that these mutations contribute to tumor development or progression as demonstrated by their evaluation in 3T3 and Ba/F3 cells. Predictive: The passage mentions the sensitivity to E7090 and erdafitinib in relation to the mutations, indicating a correlation with treatment response, which aligns with predictive evidence.

Gene→Variant (gene-first): 2261:K650E 2261:K650M 2261:S249C 2261:Y373C

Genes: 2261

Variants: K650E K650M S249C Y373C

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 16

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the effectiveness of E7090 and erdafitinib in treating tumors with specific variants, indicating a correlation between the variants and the response to these therapies. Oncogenic: The variants are described in the context of tumor growth and response to treatment, suggesting that they contribute to tumor development or progression.

Gene→Variant (gene-first): 2261:K650M 2261:K650N 2260:N546K 2263:N549K 2261:R248C

Genes: 2261 2260 2263

Variants: K650M K650N N546K N549K R248C

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 14

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the response of FGFR3 variants K650M and K650N to FGFR TKIs, indicating their sensitivity to specific therapies, which aligns with predictive evidence. Functional: The passage describes the alteration of phosphorylation status of the FGFR3 variants K650M and K650N in response to treatment, indicating a change in molecular function due to the variants.

Gene→Variant (gene-first): 2261:K650M 2261:K650N

Genes: 2261

Variants: K650M K650N

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 13

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the sensitivity and resistance of FGFR variants, including N546K and N549D/K, to FGFR inhibitors, indicating a correlation with response to therapy. Oncogenic: The passage mentions that KRAS G12V is part of a cluster composed mainly of oncogenic variants, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 3845:G12V 2260:N546K 2263:N549D/K

Genes: 3845 2260 2263

Variants: G12V N546K N549D/K

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive

Justification: Predictive: The passage discusses how different missense variants at specific amino acid positions in FGFR2 and FGFR3 correlate with varying drug sensitivities to FGFR inhibitors, indicating a relationship between the variants and treatment response.

Gene→Variant (gene-first): 2263:K656 2263:K656E/M 2263:N549 2263:N549D/H

Genes: 2263

Variants: K656 K656E/M N549 N549D/H

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 11

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the drug sensitivity of FGFR variants in response to various targeted therapies, indicating that certain variants are sensitive or resistant to specific inhibitors, which aligns with predictive evidence. Oncogenic: The context of transformed FGFR variants suggests that these somatic mutations contribute to tumor development or progression, particularly as they are assessed for their response to targeted therapies.

Gene→Variant (gene-first): 2264:N535K 2260:N546K 2263:N549D/K 2263:V550L

Genes: 2264 2260 2263

Variants: N535K N546K N549D/K V550L

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the evaluation of mRNA and protein expression levels of the R248H variant, indicating that it alters protein expression compared to oncogenic variants, which relates to its molecular function. Oncogenic: The passage implies that the R248H variant is classified as a non-oncogenic variant, contrasting it with oncogenic variants, suggesting its role in tumor development or progression is not supported.

Gene→Variant (gene-first): 1956:R248H

Genes: 1956

Variants: R248H

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the transforming potential of various FGFR variants, indicating that certain mutations contribute to tumor development or progression, as evidenced by their significant transforming activities in assays.

Gene→Variant (gene-first): 2261:G370C 2261:G380E/R 2261:K650E/M 2263:K659E 2263:N549H 2261:R248C 2261:S249C 6867:S342F 2261:S371C 2263:W290C 2261:Y373C

Genes: 2261 2263 6867

Variants: G370C G380E/R K650E/M K659E N549H R248C S249C S342F S371C W290C Y373C

[Paragraph-level] PMCID: PMC8285406 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic

Justification: Oncogenic: The V550L mutation in FGFR4 is mentioned in the context of rhabdomyosarcoma, suggesting its contribution to tumor development.

Gene→Variant (gene-first): 2260:K656E 2260:N546K 2261:S249C 2263:S252W 2263:V550L

Genes: 2260 2261 2263

Variants: K656E N546K S249C S252W V550L

[Paragraph-level] PMCID: PMC8203843 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Predictive

Justification: Predictive: The passage indicates that IDH1 R132H is associated with sensitivity to PARP inhibitors, which correlates the variant with a specific therapy response.

Gene→Variant (gene-first): 3417:R132H

Genes: 3417

Variants: R132H

[Paragraph-level] PMCID: PMC8255005 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the resistance of FLT3 mutations, specifically F691L, to FLT3 inhibitors and highlights the efficacy of KX2-391 in overcoming this resistance, indicating a correlation with treatment response. Oncogenic: The FLT3 mutations, including D835 and F691, are described as contributing to tumor development and progression in acute myeloid leukemia (AML), which supports their classification as oncogenic variants.

Gene→Variant (gene-first): 2322:D835 2322:D835Y 2322:F691 2322:F691L

Genes: 2322

Variants: D835 D835Y F691 F691L

[Paragraph-level] PMCID: PMC7785563 Section: RESULTS PassageIndex: 12

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage indicates that 90% of the cases harbored IDH1-R132H mutations, which are associated with conventional supratentorial IDH-mutant astrocytomas, suggesting a role in defining or classifying the disease. Oncogenic: The presence of IDH1-R132H mutations in the tumors suggests that this somatic variant contributes to tumor development or progression, as it is commonly found in a specific type of cancer.

Gene→Variant (gene-first): 3417:R132H

Genes: 3417

Variants: R132H

[Paragraph-level] PMCID: PMC10527017 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses the resistance of HP breast cancers to the pan-HER tyrosine kinase inhibitor, neratinib, and the effectiveness of combining neratinib with trastuzumab deruxtecan and CDK4/6 inhibitors, indicating a correlation with treatment response. Oncogenic: The study involves genetically engineered mice with the HER2V777L mutation, showing accelerated tumor formation and increased invasion, which supports the notion that this somatic variant contributes to tumor development and progression.

Gene→Variant (gene-first): 2064:V777L

Genes: 2064

Variants: V777L

[Paragraph-level] PMCID: PMC4821611 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses ALK mutations (p.C1156Y and p.G1269A) in the context of crizotinib resistance, indicating a correlation between these variants and resistance to the therapy. Oncogenic: The ALK mutations are described as being detected in post-treatment tumor samples, suggesting their contribution to tumor development or progression in the context of crizotinib resistance.

Gene→Variant (gene-first): 238:p.C1156Y 238:p.G1269A

Genes: 238

Variants: p.C1156Y p.G1269A

[Paragraph-level] PMCID: PMC4821611 Section: RESULTS PassageIndex: 10

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses mutations in the ALK gene, specifically p.C1156Y and p.G1269A, which have been reported to confer resistance against crizotinib, indicating a correlation with treatment response. Oncogenic: The presence of mutations in the ALK gene, such as p.C1156Y and p.G1269A, suggests that these somatic variants contribute to tumor development or progression, as they were identified in post-treatment tumor samples.

Gene→Variant (gene-first): 238:c.3467G>A 238:c.3806G>C 238:p.C1156Y 238:p.G1269A

Genes: 238

Variants: c.3467G>A c.3806G>C p.C1156Y p.G1269A

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 23

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the S249C and K652E mutations affect cell viability and signaling pathways, indicating that these variants alter molecular or biochemical functions related to cell growth and density. Oncogenic: The evidence suggests that the S249C and K652E mutations contribute to tumor development or progression by affecting cell cycle phases and viability, which are indicative of cancer-driving behavior.

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

Genes: 2261

Variants: K652E S249C Y762F

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 22

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the S249C+Y762F FGFR3 mutant protein's ability to induce morphological transformation and increased proliferation in NIH-3T3 cells, indicating its role in tumor development or progression. Functional: The passage describes how the S249C+Y762F mutation affects the phosphorylation of PLCgamma1 and alters the activation of downstream signaling pathways, demonstrating a change in molecular function.

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

Genes: 2261

Variants: K652E S249C Y762F

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K652E, S249C, and Y375C mutations alter the signaling response to FGF1 treatment, indicating that these variants affect molecular function related to phosphorylation and activation of signaling pathways. Oncogenic: The context of the mutations being discussed in relation to their effects on signaling pathways suggests that they may contribute to tumor development or progression, particularly given the focus on their responses in cancer-related cellular contexts.

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

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 19

Evidence Type(s): Predictive, Functional

Justification: Predictive: The passage discusses the response of cells expressing mutant FGFR3 variants (S249C, Y375C, K652E) to FGF1 stimulation, indicating a correlation with receptor activation and signaling, which relates to treatment response. Functional: The passage describes how the variants S249C, Y375C, and K652E affect the phosphorylation of FGFR3, indicating that these mutations alter the molecular function of the receptor in response to ligand stimulation.

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

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the increased phosphorylation of PLCgamma1 specifically in cells expressing the S249C and Y375C FGFR3 variants, indicating that these variants alter molecular function. Oncogenic: The mention of increased phosphorylation of signaling proteins in cells expressing the FGFR3 mutants suggests that these variants contribute to tumor development or progression.

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

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the K652E, S249C, and Y375C variants of FGFR3 alter phosphorylation levels and dimerization behavior, indicating changes in molecular function. Oncogenic: The variants are described in the context of their constitutive activation and behavior in urothelial cells, suggesting their role in tumor development or progression.

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

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the expression of proteins involved in cell survival and suggests that the K652E variant may alter the viability of cells, indicating a change in molecular function. Oncogenic: The context implies that the K652E variant contributes to tumor behavior by affecting cell viability, which is a characteristic of oncogenic variants.

Gene→Variant (gene-first): 2261:K652E

Genes: 2261

Variants: K652E

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants S249C, Y375C, and K652E FGFR3 alter the expression and phosphorylation of cell cycle-related proteins, indicating a change in molecular function.

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

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the viability of cells expressing specific variants (S249C and Y375C) compared to controls, indicating that these variants alter the molecular or biochemical function of FGFR3, affecting cell viability. Oncogenic: The evidence suggests that the variants S249C and Y375C contribute to tumor development or progression by enhancing cell viability, which is a characteristic of oncogenic behavior.

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

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 9

Evidence Type(s): Functional

Justification: Functional: The mention of K652E and Y375C variants also suggests alterations in cell cycle profiles, indicating a change in molecular function related to cell cycle dynamics.

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

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 6

Evidence Type(s): Diagnostic, Functional

Justification: Diagnostic: The passage discusses the relative frequencies of the mutations K652E, S249C, and Y375C in bladder tumors, indicating an association with the disease. Functional: The passage mentions the phenotypic effects of the variants, suggesting that they alter the behavior of cells expressing these mutations compared to controls.

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

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the expression of mutant FGFR3 variants S249C and Y375C alters the saturation density and morphology of normal urothelial cells, indicating a change in molecular or biochemical function. Oncogenic: The expression of the mutant FGFR3 variants is associated with changes in cell behavior, such as increased saturation density and altered morphology, which suggests a contribution to tumor development or progression.

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

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC2789045 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the ability of the FGFR3 mutations (S249C, Y375C, and K652E) to transform NIH-3T3 cells, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage describes how the FGFR3 mutations alter molecular function, specifically through increased phosphorylation of various proteins and changes in cell morphology and proliferation, demonstrating their biochemical activity.

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

Genes: 2261

Variants: K652E S249C Y375C

[Paragraph-level] PMCID: PMC9468105 Section: RESULTS PassageIndex: 14

Evidence Type(s): Diagnostic, Prognostic

Justification: Diagnostic: The passage discusses the association of the BRAF p.V600E mutation with pleomorphic xanthoastrocytoma, indicating its role in defining or classifying this specific tumor type. Prognostic: The Kaplan-Meier survival analysis mentioned in the passage indicates that patients with NF1-associated gliomas have inferior outcomes, suggesting a correlation between the presence of certain mutations and disease prognosis.

Gene→Variant (gene-first): 673:p.V600E

Genes: 673

Variants: p.V600E

[Paragraph-level] PMCID: PMC9468105 Section: RESULTS PassageIndex: 4

Evidence Type(s): Predisposing, Oncogenic

Justification: Predisposing: The passage describes a germline mutation (p.R1276*) associated with an autosomal dominant tumor predisposition syndrome, indicating inherited risk for developing gliomas. Oncogenic: The passage discusses the somatic inactivation of the remaining wild-type NF1 allele, which contributes to tumor development in gliomas, indicating that the variant plays a role in oncogenesis.

Gene→Variant (gene-first): 4763:c.4110 + 2 T > G 4763:p.R1276*

Genes: 4763

Variants: c.4110 + 2 T > G p.R1276*

[Paragraph-level] PMCID: PMC7068240 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses the association of high miR-31 expression with poorer mortality and shorter median survival time in patients with advanced colorectal cancer, indicating a prognostic relationship. Diagnostic: The study evaluates the potential of miRNAs as biomarkers for colorectal cancer, suggesting that the presence of the BRAF V600E mutation can be used to classify tumors based on miR-31 expression levels.

Gene→Variant (gene-first): 673:V600E 673:serine/threonine

Genes: 673

Variants: V600E serine/threonine

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 24

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the acquisition of the SF3B1 R625C, K700E, and SETBP1 E862K mutations during disease evolution, indicating their role in tumor development and progression in the context of MDS-EB transforming to AML. Functional: The mention of the SF3B1 mutations leading to changes in bone marrow morphology, such as the appearance of ring sideroblasts, suggests that these variants alter molecular or biochemical function related to the disease.

Gene→Variant (gene-first): 26040:E862K 23451:K700E 23451:R625C

Genes: 26040 23451

Variants: E862K K700E R625C

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 21

Evidence Type(s): Prognostic

Justification: Prognostic: The passage discusses the absence of the SF3B1 K700E mutation as an independent predictor of worse overall survival (OS), indicating a correlation between the variant and disease outcome.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 20

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage indicates that K700E SF3B1mut MDS showed a trend for longer overall survival (OS) compared to non-K700E SF3B1mut MDS, suggesting a correlation with disease outcome independent of therapy. Diagnostic: The passage discusses the classification of K700E SF3B1mut MDS in relation to the proposed 2020 IWG-PM criteria, indicating its use in defining or classifying a disease subtype.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 19

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage indicates that K700E SF3B1mut MDS is associated with significantly better overall survival (OS) compared to SF3B1wt MDS, suggesting a correlation with disease outcome independent of therapy. Diagnostic: The mention of K700E in the context of classifying MDS subtypes (e.g., comparing K700E SF3B1mut MDS to non-K700E SF3B1mut MDS) supports its role in defining or classifying a disease or subtype.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 18

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses the overall survival (OS) rates of K700E SF3B1mut MDS patients compared to non-K700E patients, indicating a correlation with disease outcome independent of therapy. Diagnostic: The mention of K700E SF3B1mut MDS patients in relation to non-K700E patients suggests a classification or association with a specific disease subtype.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 17

Evidence Type(s): Prognostic

Justification: Prognostic: The passage discusses overall survival (OS) in relation to the K700E variant, indicating that it correlates with disease outcome independent of therapy.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 16

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses the overall survival (OS) outcomes of K700E SF3B1mut MDS patients compared to SF3B1wt patients, indicating that the K700E variant correlates with better disease outcomes independent of therapy. Diagnostic: The K700E variant is used to classify and differentiate between SF3B1mut and SF3B1wt MDS patients, indicating its role in defining disease subtypes.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the impact of the SF3B1 K700E variant on alternative splicing events, indicating that it alters molecular function related to splicing and gene expression. Oncogenic: The SF3B1 K700E variant is associated with mutated myelodysplastic syndromes (MDS), suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Justification: Functional: The passage discusses splicing analysis related to the K700E variant, indicating an alteration in molecular function.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 12

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the classification of patients based on the presence of the K700E variant, indicating its association with lower CCSS scores, which suggests a role in defining or classifying a disease subtype. Oncogenic: The mention of the K700E variant in the context of patients with MDS (myelodysplastic syndromes) implies its contribution to tumor development or progression, as it is associated with specific cytogenetic aberrations.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 11

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 10

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the clinico-pathologic features of MDS patients with K700E mutations, indicating that these mutations are associated with specific disease characteristics and classifications, such as higher percentages of ring sideroblasts and differences in IPSS-R categories. Oncogenic: The K700E mutation in SF3B1 is implicated in the classification of MDS patients and is associated with specific tumor characteristics, suggesting its role in tumor development or progression.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 9

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 8

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the frequency of specific mutations, including K666, K700E, and R625, in patients with MDS, indicating their association with the disease and their role in defining the mutational landscape. Oncogenic: The mention of SF3B1 mutations, including K700E, K666, and R625, as frequent mutations in patients with MDS suggests that these somatic variants contribute to tumor development or progression in this context.

Gene→Variant (gene-first): 23451:K666 23451:K700E 23451:R625

Genes: 23451

Variants: K666 K700E R625

[Paragraph-level] PMCID: PMC10015977 Section: RESULTS PassageIndex: 7

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the mutational landscape of SF3B1 mutations, specifically mentioning the K700E subtype, which indicates its role in classifying or defining a disease subtype. Oncogenic: The mention of K700E in the context of SF3B1 mutations suggests its contribution to tumor development or progression, as it is associated with a specific subtype of myelodysplastic syndromes (MDS).

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 12

Evidence Type(s): Diagnostic, Prognostic

Justification: Diagnostic: The passage discusses how MDS with SF3B1 K700E mutations can be used to refine sub-classification and risk assessment criteria, indicating its role in defining or classifying a disease subtype. Prognostic: The passage states that MDS with SF3B1 K700E mutations is regarded to have a favorable prognosis, which correlates with disease outcome independent of therapy.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 10

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage indicates that SF3B1 K700E mutated MDS shows significantly better overall survival (OS) compared to non-K700E mutations, suggesting a correlation with disease outcome. Diagnostic: The mention of distinct clinicopathological and genomic characteristics associated with K700E and non-K700E SF3B1 mutations implies that the mutation type is used for risk-assessment and classification of MDS.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Diagnostic, Prognostic, Oncogenic

Justification: Diagnostic: The passage discusses the association of K700E and non-K700E mutations with specific patient characteristics and outcomes, indicating their role in classifying patients with MDS. Prognostic: The passage reports on overall survival outcomes associated with SF3B1 mutations, including K700E, indicating that these variants correlate with disease prognosis independent of therapy. Oncogenic: The mention of mutations such as K700E contributing to the classification of MDS and their association with specific patient outcomes suggests a role in tumor development or progression.

Gene→Variant (gene-first): 23451:K666 23451:K700 23451:K700E 23451:R625

Genes: 23451

Variants: K666 K700 K700E R625

[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the analysis of clinical-pathologic features and outcomes in MDS patients, specifically exploring differences between K700E and non-K700E variants, indicating a potential role in classification or association with disease characteristics. Oncogenic: The mention of analyzing the clinical-pathologic features of SF3B1mut patients, including K700E, suggests that this variant may contribute to tumor development or progression in the context of MDS.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC10015977 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage states that SF3B1 mutations, including K700E, have a favorable prognosis in myelodysplastic syndromes, indicating a correlation with disease outcome. Diagnostic: The mention of SF3B1 mutations in the context of myelodysplastic syndromes suggests that these mutations, including K700E, are used to classify or define the disease.

Gene→Variant (gene-first): 23451:K700E

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC3141770 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage indicates that the H1047R mutation is associated with PTEN loss in patients, suggesting that it contributes to tumor development or progression.

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

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC3141770 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the incidence of PIK3CA mutations and their occurrence in specific samples, indicating their association with the disease. Oncogenic: The mention of PIK3CA mutations, including E542K and H1047R, suggests their role in tumor development, as they are described as mutations found in tumor samples.

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

Genes: 5290 5728

Variants: E542K H1047R T1052A

[Paragraph-level] PMCID: PMC5652823 Section: ABSTRACT PassageIndex: 7

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage indicates that patients with the EGFR-T790M mutation responded to the 3rd-generation EGFR-TKI osimertinib, suggesting a correlation between the variant and treatment response. Diagnostic: The EGFR-T790M mutation is mentioned as being revealed in re-biopsies at progression, indicating its role in defining or confirming the presence of a specific disease state in patients treated with EGFR-TKIs.

Gene→Variant (gene-first): 1956:T790M

Genes: 1956

Variants: T790M

[Paragraph-level] PMCID: PMC5122709 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses the effectiveness of BRAF inhibitors in patients with metastatic melanoma harboring BRAF V600 mutations, indicating a correlation with treatment response. Diagnostic: The BRAF V600 mutation is used to define and classify patients with metastatic melanoma, as all patients in the study had BRAFV600E mutations.

Gene→Variant (gene-first): 673:V600

Genes: 673

Variants: V600

[Paragraph-level] PMCID: PMC1952070 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses mutations, including the L858R point mutation, in the context of their correlation with response to treatment, indicating a predictive relationship. Diagnostic: The mention of the L858R mutation as part of a group of mutations previously correlated with response suggests its role in defining or classifying a disease subtype.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how mutations at amino acids p.Glu542 and p.His1047 increase intracellular AKT phosphorylation, indicating an alteration in molecular function related to AKT activation. Oncogenic: The mention of increased AKT phosphorylation due to the H1047R mutation suggests that this somatic variant contributes to tumor development or progression by promoting cellular processes such as survival and proliferation.

Gene→Variant (gene-first): 5290:H1047R 5290:p.Glu542 5290:p.His1047

Genes: 5290

Variants: H1047R p.Glu542 p.His1047

[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses somatic mutations in the PIK3CA gene, specifically mentioning that the E542K, H1047R, and H1047L mutations are known gain-of-function mutations frequently mutated in cancer, indicating their contribution to tumor development or progression. Functional: The passage notes that the mutations E542K and H1047 (both H1047R and H1047L) are located in the helical and kinase domains of the PI3K protein, which are known hotspots for somatic gain-of-function mutations, suggesting that these variants alter the molecular function of the protein.

Gene→Variant (gene-first): 5290:E542K 5290:H1047L 5290:H1047R 5163:R115P 5290:p.Glu542 5290:p.His1047

Genes: 5290 5163

Variants: E542K H1047L H1047R R115P p.Glu542 p.His1047

[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 5

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The R115P mutation in PIK3CA is suggested as a likely candidate for macrodactyly, indicating its association with a specific disease. Oncogenic: The R115L mutation is annotated in a database of somatic mutations in cancer, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): 5290:R115L 5163:R115P 5290:p.Arg115

Genes: 5290 5163

Variants: R115L R115P p.Arg115

[Paragraph-level] PMCID: PMC3542862 Section: RESULTS PassageIndex: 4

Evidence Type(s): Diagnostic, Oncogenic

Justification: Diagnostic: The passage discusses the presence of the R115P mutation in PIK3CA in lesional tissue but not in blood, indicating its potential role in defining or confirming a disease state. Oncogenic: The R115P mutation in PIK3CA is described as potentially deleterious and is present in lesional tissue, suggesting it contributes to tumor development or progression.

Gene→Variant (gene-first): 91544:C392G 5163:R115P

Genes: 91544 5163

Variants: C392G R115P

[Paragraph-level] PMCID: PMC2837563 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses K-Ras mutations identified in tumors, indicating that these variants contribute to tumor development or progression, particularly with reference to their phenotypes in the context of cancer. Functional: The passage describes the phenotypic effects of the K-Ras mutations, suggesting that they alter molecular or biochemical function, as evidenced by the comparison of their phenotypes to hotspot mutations and wild-type K-Ras.

Gene→Variant (gene-first): 3845:Ala146Thr 3845:Arg164Gln 3845:Leu19Phe 3845:Lys117Asn

Genes: 3845

Variants: Ala146Thr Arg164Gln Leu19Phe Lys117Asn

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 20

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how specific amino acid substitutions at G12, G13, and Q61 alter biochemical properties and mechanisms across RAS proteins, indicating a change in molecular function related to GTP hydrolysis and downstream signaling. Oncogenic: The mention of hotspot variants and their clustering patterns suggests that these somatic variants contribute to tumor development or progression, particularly in the context of their distinct biochemical properties and disease incidence.

Gene→Variant (gene-first): 3845:G12 3845:G13 3845:Q61

Genes: 3845

Variants: G12 G13 Q61

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how different KRAS mutations, including G12C/D and G12D, affect downstream activity and enzyme function, as demonstrated by Western blot analyses measuring pERK levels. Oncogenic: The mention of KRAS hotspot variants and their distinct effects on downstream signaling suggests that these somatic mutations contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:G12 3845:G12C 3845:G12C/D 3845:G12D 3845:G13 3845:Q61

Genes: 3845

Variants: G12 G12C G12C/D G12D G13 Q61

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional, Predictive

Justification: Functional: The passage discusses how specific amino acid substitutions affect RAF affinity, indicating that these variants alter molecular function related to protein interactions. Predictive: The passage predicts changes in RAF affinity for various variants, suggesting a correlation with potential therapeutic responses or resistance based on their affinity levels.

Gene→Variant (gene-first): 3265:A146V 673:A18D 3265:A59T 3845:G12 3845:G12S 3845:G13C 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P

Genes: 3265 673 3845 4893 22882

Variants: A146V A18D A59T G12 G12S G13C G13V K117N L19F Q22K Q61H Q61P Q61R R164Q T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the KRAS variants alter RAF affinity, indicating that these variants affect molecular function, specifically in relation to protein interactions and binding properties. Oncogenic: The context of the variants being associated with RAF affinity suggests a role in tumor development or progression, as RAF is a key component in signaling pathways that drive cancer.

Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12C 3845:G12C/D 3845:G12R 3845:G13C/D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H/L 3845:Q61P 4893:Q61R 3845:R164Q 22882:T74P 22882:V/A

Genes: 3845 3265 673 4893 22882

Variants: A146T A146V A18D A59T G12C G12C/D G12R G13C/D G13V K117N L19F Q22K Q61H/L Q61P Q61R R164Q T74P V/A

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Predictive, Oncogenic

Justification: Functional: The passage discusses how mutated KRAS proteins may alter GAP binding and change GAP-mediated hydrolysis rates, indicating that the variants affect molecular function. Predictive: The analysis provides a probability density distribution and suggests that the variants can predict relative levels for mutations based on their GAP-mediated hydrolysis rates, indicating a correlation with functional outcomes. Oncogenic: The context of the variants being associated with cancer and their effects on GAP-mediated hydrolysis suggests that these somatic variants contribute to tumor development or progression.

Gene→Variant (gene-first): 3845:A146T 3265:A146V 673:A18D 3265:A59T 3845:G12A/R 3845:G12D 3845:G12S 3845:G13C 3845:G13D 3265:G13V 3845:K117N 3845:L19F 3845:Q22K 3845:Q61H 22882:T74P

Genes: 3845 3265 673 22882

Variants: A146T A146V A18D A59T G12A/R G12D G12S G13C G13D G13V K117N L19F Q22K Q61H T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Justification: Functional: The passage discusses how mutations, including G13C, A146V, K117N, and G13V, alter local stability and modulate local unfolding, indicating a change in molecular function related to the hydrolysis rate.

Gene→Variant (gene-first): 3265:A146V 3845:G13C 3265:G13V 3845:K117N

Genes: 3265 3845

Variants: A146V G13C G13V K117N

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional, Diagnostic

Justification: Functional: The passage discusses how various KRAS variants, including both hotspot and non-hotspot mutations, exhibit distinct profiles and behaviors based on experimental measurements, indicating that these variants alter molecular or biochemical function. Diagnostic: The mention of clustering variants and their association with specific profiles suggests that these variants can be used to classify or define differences in behavior, which aligns with diagnostic evidence.

Gene→Variant (gene-first): 3845:A146T 3845:A146T/V 3265:A59T 3845:G12A/R 3845:G12A/R/S 3845:G12V/D 3845:G13C 3845:G13V/D 673:K177N 3845:L19F 3845:Q22K 3845:Q61 3845:Q61H 3845:Q61L/P 3845:R164Q 22882:T74P

Genes: 3845 3265 673 22882

Variants: A146T A146T/V A59T G12A/R G12A/R/S G12V/D G13C G13V/D K177N L19F Q22K Q61 Q61H Q61L/P R164Q T74P

[Paragraph-level] PMCID: PMC8688876 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Justification: Functional: The passage discusses how various KRAS variants, including G12, G12V, G13, Q61, and T74, affect biochemical properties such as GTP binding, nucleotide exchange, and hydrolysis, indicating that these variants alter molecular or biochemical function.

Gene→Variant (gene-first): 3845:G12 3845:G12V 3845:G13 3845:Q61 22882:T74

Genes: 3845 22882

Variants: G12 G12V G13 Q61 T74

[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 15

Evidence Type(s): Prognostic, Predictive

Justification: Prognostic: The passage discusses how the rs3786362 variant correlates with progression-free survival (PFS) and overall survival (OS) in metastatic colorectal cancer (mCRC) patients, indicating its association with disease outcomes independent of therapy. Predictive: The passage suggests that TYMS rs3786362 could be a predictive biomarker for survival in mCRC patients, indicating a potential correlation with treatment response in specific subgroups.

Gene→Variant (gene-first): 7298:rs3786362

Genes: 7298

Variants: rs3786362

[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 14

Evidence Type(s): Prognostic

Justification: Prognostic: The passage indicates that rs3786362 is involved in stratification analysis related to mCRC survival, suggesting a correlation with disease outcome.

Gene→Variant (gene-first): 7298:rs3786362

Genes: 7298

Variants: rs3786362

[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 13

Evidence Type(s): Predictive

Justification: Predictive: The passage discusses the correlation of the variant rs3786362 with responses to first-line chemotherapy in mCRC patients, indicating that the G allele is associated with reduced disease control rate (DCR), which relates to treatment response.

Gene→Variant (gene-first): 7298:rs3786362

Genes: 7298

Variants: rs3786362

[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 12

Evidence Type(s): Predictive

Justification: Predictive: The passage discusses the correlation between the variant rs3786362 and the disease control rate (DCR) in metastatic colorectal cancer (mCRC) patients, indicating a relationship with treatment response.

Gene→Variant (gene-first): 7298:rs3786362

Genes: 7298

Variants: rs3786362

[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 11

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses the correlation of the rs3786362 variant with progression-free survival (PFS) and overall survival (OS) in mCRC patients, indicating its association with disease outcome independent of therapy. Diagnostic: The variant rs3786362 is used to classify patients based on their genotypes (AG/GG vs. AA), which suggests its role in defining or associating with a disease subtype in mCRC.

Gene→Variant (gene-first): 7298:rs3786362

Genes: 7298

Variants: rs3786362

[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 10

Evidence Type(s): Prognostic, Diagnostic

Justification: Prognostic: The passage discusses the association of the variant rs3786362 with reduced overall survival (OS) and progression-free survival (PFS), indicating its correlation with disease outcomes independent of therapy. Diagnostic: The variant rs3786362 is associated with different genotypes (AG and AA) that correlate with reduced PFS and OS, suggesting its role in classifying disease outcomes based on genotype.

Gene→Variant (gene-first): 7298:rs3786362

Genes: 7298

Variants: rs3786362

[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 9

Evidence Type(s): Prognostic

Justification: Prognostic: The passage discusses the correlation between the variant rs3786362 and mCRC survival, indicating its association with disease outcome independent of therapy.

Gene→Variant (gene-first): 7298:rs3786362

Genes: 7298

Variants: rs3786362

[Paragraph-level] PMCID: PMC7545690 Section: RESULTS PassageIndex: 8

Evidence Type(s): Prognostic, Predictive

Justification: Prognostic: The passage discusses the correlation of SNPs, specifically rs3786362 and rs369803, with progression-free survival (PFS) in metastatic colorectal cancer (mCRC) patients, indicating their association with disease outcome. Predictive: The passage mentions the correlation of SNPs with disease control rate (DCR), suggesting that these variants may influence treatment response in mCRC patients.

Gene→Variant (gene-first): 10841:rs10432965 2346:rs369803 7298:rs3786362 113235:rs4795436

Genes: 10841 2346 7298 113235

Variants: rs10432965 rs369803 rs3786362 rs4795436

[Paragraph-level] PMCID: PMC7325368 Section: ABSTRACT PassageIndex: 6

Evidence Type(s): Predictive, Diagnostic

Justification: Predictive: The passage discusses the response of patients with B-RAFV600E mutations to therapy, indicating a correlation between the variant and treatment outcomes in various cancers. Diagnostic: The mention of B-RAFV600E in the context of specific cancer types suggests its use as a biomarker to classify or define these diseases.

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

Genes: 673

Variants: B-RAFV600E

[Paragraph-level] PMCID: PMC7325368 Section: ABSTRACT PassageIndex: 2

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The passage discusses lifirafenib as an inhibitor specifically targeting B-RAFV600E, indicating a correlation with response to therapy in patients with B-RAF-mutated tumors. Oncogenic: The mention of B-RAFV600E in the context of mutated solid tumors suggests that this somatic variant contributes to tumor development or progression.

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

Genes: 673

Variants: B-RAFV600E

[Paragraph-level] PMCID: PMC8033310 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the establishment of TNBC cell lines with PIK3CA gene mutations (E545K and H1047R) and their use in in vivo experiments, indicating that these somatic variants contribute to tumor development or progression. Functional: The passage mentions the use of various assays (e.g., western blot, quantitative reverse transcription-polymerase chain reaction) to detect gene and protein expression levels, suggesting that the variants may alter molecular or biochemical function.

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

Genes: 5290

Variants: E545K H1047R