[Paragraph-level] PMCID: PMC7612475 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Predictive, Functional, Oncogenic

Summary: Evidence Type: Predictive | Mutation: K700E | Summary: The K700E mutation in SF3B1 increases cellular sensitivity to ionising radiation and various chemotherapeutic agents, including PARP inhibitors, suggesting a correlation with treatment response. Evidence Type: Functional | Mutation: K700E | Summary: The K700E mutation alters molecular function by compromising homologous recombination efficiency and inducing unscheduled R-loop formation, replication fork stalling, and defective replication fork restart. Evidence Type: Oncogenic | Mutation: K700E | Summary: The K700E mutation contributes to tumor development by inducing a BRCA-like cellular phenotype that confers synthetic lethality to DNA damaging agents and PARP inhibitors.

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

Genes: 23451

Variants: K700E

[Paragraph-level] PMCID: PMC9900321 Section: ABSTRACT PassageIndex: 3

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: Gly-to-Asp | Summary: The Gly-to-Asp mutation (KRASG12D) is associated with the efficacy of the small-molecule KRASG12D inhibitor, MRTX1133, indicating a correlation with treatment response in pancreatic ductal adenocarcinoma models. Evidence Type: Oncogenic | Mutation: Gly-to-Asp | Summary: The Gly-to-Asp mutation (KRASG12D) is prevalent in pancreatic ductal adenocarcinoma and contributes to tumor development and progression, as evidenced by its high occurrence in patients with this cancer type.

Gene→Variant (gene-first): 3845:Gly-to-Asp

Genes: 3845

Variants: Gly-to-Asp

[Paragraph-level] PMCID: PMC3542862 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: E542K | Summary: The E542K mutation in PIK3CA is identified as a gain-of-function mutation contributing to tumor development in the affected nerve tissue of patients with macrodactyly. Evidence Type: Oncogenic | Mutation: H1047L | Summary: The H1047L mutation in PIK3CA is identified as a gain-of-function mutation contributing to tumor development in the affected nerve tissue of patients with macrodactyly. Evidence Type: Oncogenic | Mutation: H1047R | Summary: The H1047R mutation in PIK3CA is identified as a gain-of-function mutation contributing to tumor development in the affected nerve tissue of patients with macrodactyly. Evidence Type: Oncogenic | Mutation: R115P | Summary: The R115P mutation in PIK3CA is confirmed as a somatic mutation present in the affected nerve tissue, contributing to the pathophysiology of macrodactyly.

Gene→Variant (gene-first): 5290:E542K 5290:H1047L 5290:H1047R 5163:R115P

Genes: 5290 5163

Variants: E542K H1047L H1047R R115P

[Paragraph-level] PMCID: PMC5822176 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Prognostic, Oncogenic

Summary: Evidence Type: Prognostic | Mutation: K27M | Summary: The H3 K27M mutation has been associated with longer survival in some patients with tumors of alternate morphologies, indicating a potential correlation with disease outcome independent of therapy. Evidence Type: Oncogenic | Mutation: K27M | Summary: The H3 K27M mutation contributes to tumor development and progression, as it is implicated in various types of gliomas, including pediatric diffuse intrinsic pontine gliomas and adult midline diffuse gliomas.

Gene→Variant (gene-first): 3417:K27M

Genes: 3417

Variants: K27M

[Paragraph-level] PMCID: PMC4999563 Section: ABSTRACT PassageIndex: 9

Evidence Type(s): Prognostic

Summary: Evidence Type: Prognostic | Mutation: G12C | Summary: The KRAS G12C mutation is associated with poor survival outcomes in mCRC patients compared to those with non-mutated tumors. Evidence Type: Prognostic | Mutation: G13D | Summary: The KRAS G13D mutation is associated with poor survival outcomes in mCRC patients compared to those with non-mutated tumors.

Gene→Variant (gene-first): 3845:G12C 3845:G13D

Genes: 3845

Variants: G12C G13D

[Paragraph-level] PMCID: PMC4999563 Section: ABSTRACT PassageIndex: 7

Evidence Type(s): Prognostic

Summary: Evidence Type: Prognostic | Mutation: G12C | Summary: The KRAS G12C variant is associated with inferior overall survival (OS) compared to unmutated tumors, indicating a prognostic role. Evidence Type: Prognostic | Mutation: G13D | Summary: The KRAS G13D variant shows a similar trend for inferior overall survival (OS), suggesting it may also have prognostic implications. Evidence Type: Prognostic | Mutation: G12D | Summary: The KRAS G12D variant did not show a significant impact on overall survival (OS), indicating it may not have a strong prognostic role. Evidence Type: Prognostic | Mutation: G12V | Summary: The KRAS G12V variant also did not demonstrate a significant impact on overall survival (OS), suggesting limited prognostic value.

Gene→Variant (gene-first): 3845:G12C 3845:G12D 3845:G12V 3845:G13D

Genes: 3845

Variants: G12C G12D G12V G13D

[Paragraph-level] PMCID: PMC4999563 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Prognostic

Summary: Evidence Type: Prognostic | Mutation: G12C | Summary: The KRAS G12C mutation is associated with inferior progression-free and overall survival in metastatic colorectal cancer patients compared to those with non-mutated tumors. Evidence Type: Prognostic | Mutation: G13D | Summary: The KRAS G13D mutation is associated with inferior progression-free and overall survival in metastatic colorectal cancer patients compared to those with non-mutated tumors.

Gene→Variant (gene-first): 3845:G12C 3845:G13D

Genes: 3845

Variants: G12C G13D

[Paragraph-level] PMCID: PMC9837058 Section: ABSTRACT PassageIndex: 1

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: G1049R | Summary: The G1049R mutation is described as activating p110alpha through distinct mechanisms, indicating its role in tumor development or progression. Evidence Type: Oncogenic | Mutation: H1047R | Summary: The H1047R mutation is noted to activate p110alpha, contributing to tumor development or progression. Evidence Type: Oncogenic | Mutation: M1043I/L | Summary: The M1043I/L mutations are mentioned as activating p110alpha, which suggests their involvement in tumor development or progression.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043I/L

Genes: 5290

Variants: G1049R H1047R M1043I/L

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 19

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation shows unique differences in binding interactions upon pY binding, suggesting alterations in molecular function related to the regulatory motif of the protein.

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

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 18

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: H1047R | Summary: The H1047R mutation contributes to tumor development by leading to activation through disruption of the inhibitory conformation of the C-terminal tail. Evidence Type: Oncogenic | Mutation: G1049R | Summary: The G1049R mutation contributes to tumor development by leading to activation through disruption of the inhibitory conformation of the C-terminal tail.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 17

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation is associated with alterations in molecular or biochemical function, as indicated by the analysis of perturbations in conformation observed in the HDX-MS experiments.

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

Genes: 5290

Variants: H1047R

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: M1043L | Summary: The M1043L mutation alters molecular or biochemical function as it is described in the context of kinase activity. Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation alters molecular or biochemical function as it is described in the context of kinase activity. Evidence Type: Functional | Mutation: G1049R | Summary: The G1049R mutation alters molecular or biochemical function as it is described in the context of kinase activity. Evidence Type: Functional | Mutation: N1068fs | Summary: The N1068fs mutation alters molecular or biochemical function as it is described in the context of being a kinase dead variant.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation alters molecular function by enhancing membrane binding and increasing basal ATPase activity. Evidence Type: Functional | Mutation: G1049R | Summary: The G1049R mutation alters molecular function by enhancing membrane binding and increasing basal ATPase activity. Evidence Type: Functional | Mutation: N1068fs | Summary: The N1068fs mutation alters molecular function by increasing membrane binding without affecting basal ATPase activity. Evidence Type: Functional | Mutation: M1043L | Summary: The M1043L mutation alters molecular function by increasing basal ATPase activity with a limited effect on membrane binding.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: G1049R | Summary: The G1049R mutation shows significantly increased ATPase activity compared to wild type, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: H1047R | Summary: The H1047R mutation exhibits significantly increased ATPase activity compared to wild type, suggesting a change in molecular function. Evidence Type: Functional | Mutation: M1043L | Summary: The M1043L mutation demonstrates significantly increased ATPase activity compared to wild type, reflecting an alteration in molecular function.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:M1043L 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R M1043L N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 12

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: H1047R/L | Summary: H1047R/L is identified as the most frequent oncogenic mutation, contributing to tumor development or progression. Evidence Type: Oncogenic | Mutation: M1043L/I | Summary: M1043L/I is a frequent missense mutation that is associated with oncogenic behavior in tumor samples. Evidence Type: Oncogenic | Mutation: G1049R | Summary: G1049R is noted as a frequent missense mutation that contributes to tumor development or progression. Evidence Type: Oncogenic | Mutation: N1068fs | Summary: N1068fs is an activating frameshift variant that alters the C-terminus and is associated with oncogenic behavior in tumor samples.

Gene→Variant (gene-first): 5290:G1049R 5290:H1047R 5290:H1047R/L 5290:M1043L 5290:M1043L/I 5290:N1044K 5290:N1068fs

Genes: 5290

Variants: G1049R H1047R H1047R/L M1043L M1043L/I N1044K N1068fs

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 11

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: H1047R | Summary: The H1047R mutation is described as an oncogenic mutation that contributes to tumor development by increasing membrane binding through alterations in the kinase domain structure. Evidence Type: Functional | Mutation: His1047 | Summary: His1047 is involved in extensive interactions within the kinase domain, indicating that it plays a role in the molecular function of the protein. Evidence Type: Functional | Mutation: Met1043 | Summary: Met1043 is mentioned as a hydrophobic residue that contributes to the structural integrity of the kinase domain, suggesting its role in the molecular function of the protein.

Gene→Variant (gene-first): 5290:H1047R 5290:His1047 5290:Met1043

Genes: 5290

Variants: H1047R His1047 Met1043

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: E726K | Summary: The mutation E726K is mentioned in the context of oncogenic mutations, indicating its potential contribution to tumor development or progression, as it is part of a comparison with other missense oncogenic mutations. Evidence Type: Functional | Mutation: E726K | Summary: The passage discusses conformational changes associated with the E726K mutation, suggesting that it alters molecular or biochemical function, particularly in relation to the disengagement of the ABD and p85 from the catalytic core.

Gene→Variant (gene-first): 5290:E726K

Genes: 5290

Variants: E726K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: N345K | Summary: The N345K mutation in p110alpha is associated with altered membrane binding properties, as evidenced by HDX-MS experiments showing protection in specific regions of the protein when interacting with membranes. This indicates a change in molecular function related to membrane association.

Gene→Variant (gene-first): 5290:N345K

Genes: 5290

Variants: N345K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 4

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: N345K | Summary: The N345K mutation is associated with increased membrane binding for oncogenic mutants, suggesting it contributes to tumor development or progression. Evidence Type: Oncogenic | Mutation: G106V | Summary: The G106V mutation is linked to increased membrane binding for oncogenic mutants, indicating its role in tumor development or progression. Evidence Type: Oncogenic | Mutation: G118D | Summary: The G118D mutation is associated with increased membrane binding for oncogenic mutants, suggesting it contributes to tumor development or progression.

Gene→Variant (gene-first): 5290:G106V 5290:G118D 5290:N345K

Genes: 5290

Variants: G106V G118D N345K

[Paragraph-level] PMCID: PMC9837058 Section: RESULTS PassageIndex: 2

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: D915N | Summary: The D915N mutation is described as a kinase dead mutation that does not cause significant changes in protein conformation or membrane binding, indicating its role in altering molecular function without affecting these properties.

Gene→Variant (gene-first): 5290:D915N

Genes: 5290

Variants: D915N

[Paragraph-level] PMCID: PMC6280667 Section: RESULTS PassageIndex: 9

Evidence Type(s): Predictive

Summary: Evidence Type: Predictive | Mutation: TP53 | Summary: TP53 mutations were shown to cause a broad pattern of drug resistance, with some drugs trending more sensitive to TP53 mutant cases, indicating a correlation with treatment response. Evidence Type: Predictive | Mutation: ASXL1 | Summary: ASXL1 mutations were associated with drug resistance, but also showed sensitivity to specific drugs, suggesting a predictive role in treatment response. Evidence Type: Predictive | Mutation: NRAS | Summary: NRAS mutations correlated largely with resistance to most drugs, but also showed predicted sensitivity to MAPK inhibitors, indicating a potential predictive value for therapy. Evidence Type: Predictive | Mutation: KRAS | Summary: KRAS mutations were associated with resistance to most drugs, while also showing sensitivity to MAPK inhibitors, suggesting a predictive role in treatment response. Evidence Type: Predictive | Mutation: IDH2 | Summary: IDH2 mutations conferred sensitivity to a broad spectrum of drugs, indicating a predictive association with treatment response. Evidence Type: Predictive | Mutation: IDH1 | Summary: IDH1 mutations were associated with resistance to most drugs, suggesting a predictive role in treatment response. Evidence Type: Predictive | Mutation: RUNX1 | Summary: RUNX1 mutations correlated with sensitivity to PIK3C/MTOR inhibitors, indicating a predictive association with treatment response. Evidence Type: Predictive | Mutation: FLT3 | Summary: FLT3 mutations exhibited a significant pattern of co-occurrence with sensitivity to the FDA approved drug, ibrutinib, indicating a predictive role in treatment response. Evidence Type: Predictive | Mutation: NPM1 | Summary: NPM1 mutations were significantly more sensitive to ibrutinib compared to wild type, suggesting a predictive association with treatment response. Evidence Type: Predictive | Mutation: BCOR | Summary: BCOR mutations showed sensitivity to alternative drugs, indicating a predictive role in treatment response, particularly in specific combinatorial mutation settings.

Gene→Variant (gene-first): 8233:serine/arginine

Genes: 8233

Variants: serine/arginine

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: E401G | Summary: The E401G mutation in ERBB2 is associated with increased tumor growth in vivo, indicating its role in tumor development or progression. Evidence Type: Functional | Mutation: E401G | Summary: The E401G mutation alters the molecular function of ERBB2, contributing to enhanced tumor-forming capacity.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 16

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E401G | Summary: The variant ERBB2 E401G alters the proliferative and invasive capacities of cancer cells, indicating a change in molecular function. Evidence Type: Functional | Mutation: S310F | Summary: The variant ERBB2 S310F is associated with a significantly higher proliferation rate in cancer cells, suggesting an alteration in molecular function.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 15

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E401G | Summary: The passage suggests that the ERBB2 E401G variant has biological effects, indicating that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 14

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E401G | Summary: The E401G mutation alters molecular signaling activity by activating the MAPK pathway, as evidenced by elevated phosphorylation of ERK in cells expressing this variant. Evidence Type: Functional | Mutation: S310F | Summary: The S310F mutation also alters molecular signaling activity by activating the MAPK pathway, demonstrated by increased phosphorylation of ERK in cells expressing this variant.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 12

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E401G | Summary: The E401G mutation appears to stabilize the dimer interface of the HER2-EGFR complex, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: S310F | Summary: The S310F mutation also seems to stabilize the dimer interface of the HER2-EGFR complex, suggesting a change in molecular function.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 11

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E401G | Summary: The E401G mutation is analyzed in the context of HER-family dimers, suggesting it alters the molecular interactions and stability of these complexes. Evidence Type: Functional | Mutation: S310F | Summary: The S310F mutation is examined for its role in the formation and stability of HER-family dimers, indicating a potential alteration in molecular function.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 10

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: p.(E401G) | Summary: The mutation p.(E401G) alters the molecular function by stabilizing the ligand-free EGFR HER2 heterodimer.

Gene→Variant (gene-first): 2176:p.(E401G)

Genes: 2176

Variants: p.(E401G)

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 9

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: E401G | Summary: The HER2 E401G mutation is associated with increased phosphorylation levels of HER2 and EGFR, suggesting its role in tumor development or progression. Evidence Type: Oncogenic | Mutation: S310F | Summary: The HER2 S310F mutation is linked to increased phosphorylation levels of HER2 and EGFR, indicating its contribution to tumor development or progression.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 8

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E401G | Summary: The E401G mutation is associated with the identification of potential dimerization partners of the HER2 protein, indicating an alteration in molecular function.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 7

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: S310F | Summary: The S310F variant is associated with robust elevation of C-terminal phosphorylation of HER2, indicating an alteration in molecular function. Evidence Type: Functional | Mutation: E401G | Summary: The E401G variant also shows increased phosphorylation of HER2, suggesting a change in molecular function, although the effect is less pronounced than that of S310F.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 6

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E321G | Summary: The E321G variant is associated with the ability to form disulfide-linked dimers, indicating a change in molecular function. Evidence Type: Functional | Mutation: E401G | Summary: The E401G variant does not contribute to the formation of disulfide-linked dimers, suggesting an alteration in molecular function. Evidence Type: Functional | Mutation: S310F | Summary: The S310F variant also does not show increases in HER2 dimers, indicating a change in molecular function.

Gene→Variant (gene-first): 7157:E321G 2176:E401G 2064:S310F

Genes: 7157 2176 2064

Variants: E321G E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 5

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E401G | Summary: The E401G variant of ERBB2 was evaluated for its functional properties, specifically its mechanisms of activation related to disulfide-linked dimer formation and C-terminal phosphorylation. Evidence Type: Functional | Mutation: E321G | Summary: The E321G variant of ERBB2 was included in the evaluation of functional properties related to activation mechanisms, focusing on disulfide-linked dimers and C-terminal phosphorylation. Evidence Type: Functional | Mutation: S310F | Summary: The S310F variant of ERBB2 was assessed for its functional properties, particularly in the context of activation mechanisms involving disulfide-linked dimers and C-terminal phosphorylation. Evidence Type: Functional | Mutation: D845A | Summary: The D845A variant of ERBB2, described as a kinase domain inactivating variant, was part of the evaluation of functional properties related to activation mechanisms.

Gene→Variant (gene-first): 2064:D845A 7157:E321G 2176:E401G 2064:S310F

Genes: 2064 7157 2176

Variants: D845A E321G E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E401G | Summary: The variant E401G is described as having functional properties, indicating that it alters molecular or biochemical function. Evidence Type: Functional | Mutation: S310F | Summary: The variant S310F is noted to have functional properties similar to E401G, suggesting it also alters molecular or biochemical function.

Gene→Variant (gene-first): 2176:E401G 2064:S310F

Genes: 2176 2064

Variants: E401G S310F

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 3

Evidence Type(s): Oncogenic, Functional

Summary: Evidence Type: Oncogenic | Mutation: E401G | Summary: The ERBB2 E401G variant is identified as a somatic mutation that contributes to tumor development, as indicated by its high allele fraction and association with ERBB2 gene amplification. Evidence Type: Functional | Mutation: E401G | Summary: Computational tools suggest that the ERBB2 E401G variant alters the molecular function of the encoded gene product, indicating a deleterious effect.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

[Paragraph-level] PMCID: PMC8881279 Section: RESULTS PassageIndex: 2

Evidence Type(s): Diagnostic

Summary: Evidence Type: Diagnostic | Mutation: E401G | Summary: The ERBB2 E401G variant is detected in a patient with cancer of unknown primary (CUP), suggesting its role in defining or classifying the disease.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

[Paragraph-level] PMCID: PMC6938308 Section: RESULTS PassageIndex: 2

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: p.12G | Summary: The somatic mutation p.12G in KRAS has been linked to brain AVMs, indicating its contribution to tumor development. Evidence Type: Oncogenic | Mutation: p.600V | Summary: The somatic mutation p.600V in BRAF has been linked to brain AVMs, indicating its contribution to tumor development. Evidence Type: Oncogenic | Mutation: p.G12D | Summary: The somatic mutation p.G12D in KRAS has been identified in multiple AVM specimens, suggesting its role in tumor progression. Evidence Type: Oncogenic | Mutation: p.G12V | Summary: The somatic mutation p.G12V in KRAS has been identified in multiple AVM specimens, suggesting its role in tumor progression. Evidence Type: Oncogenic | Mutation: p.Q636X | Summary: The somatic mutation p.Q636X in BRAF has been linked to brain AVMs, indicating its contribution to tumor development. Evidence Type: Oncogenic | Mutation: p.V600E | Summary: The somatic mutation p.V600E in BRAF has been linked to brain AVMs, indicating its contribution to tumor development.

Gene→Variant (gene-first): 3845:p.12G 673:p.600V 3845:p.G12D 3845:p.G12V 673:p.Q636X 673:p.V600E

Genes: 3845 673

Variants: p.12G p.600V p.G12D p.G12V p.Q636X p.V600E

[Paragraph-level] PMCID: PMC8307492 Section: ABSTRACT PassageIndex: 4

Evidence Type(s): Predictive, Prognostic

Summary: Evidence Type: Predictive | Mutation: L858R | Summary: The L858R mutation is associated with response to first-line EGFR inhibitors, with survival outcomes indicating it may not perform as well as exon 19 deletions in terms of overall survival (OS). Evidence Type: Prognostic | Mutation: L858R | Summary: The L858R mutation correlates with overall survival outcomes in non-small-cell lung cancer (NSCLC) patients, independent of therapy, suggesting its relevance in disease prognosis.

Gene→Variant (gene-first): 1956:L858R

Genes: 1956

Variants: L858R

[Paragraph-level] PMCID: PMC10805385 Section: RESULTS PassageIndex: 17

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: G12C | Summary: The G12C mutation in KRAS is associated with tumor development, as indicated by its presence in primary KRAS-mutant tumors and patient-derived xenograft models. Evidence Type: Oncogenic | Mutation: G245V | Summary: The G245V mutation in TP53 is present in a KRAS-mutant tumor context, suggesting its contribution to tumor development and progression in the analyzed patient-derived xenograft models.

Gene→Variant (gene-first): 3845:G12C 7157:G245V

Genes: 3845 7157

Variants: G12C G245V

[Paragraph-level] PMCID: PMC10690049 Section: RESULTS PassageIndex: 7

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: G12D | Summary: The KRASG12D mutation was tested in the context of a drug combination, indicating a potential correlation with resistance to therapy, as the KRASG12D MEFs were refractory to growth inhibition. Evidence Type: Oncogenic | Mutation: G12D | Summary: The KRASG12D mutation is associated with tumor development or progression, as it is mentioned in the context of MEFs that are used to study cancer behavior.

Gene→Variant (gene-first): 3845:G12D

Genes: 3845

Variants: G12D

[Paragraph-level] PMCID: PMC10690049 Section: RESULTS PassageIndex: 6

Evidence Type(s): Predictive, Oncogenic

Summary: Evidence Type: Predictive | Mutation: G12C | Summary: The KRAS G12C mutation is associated with sensitivity to specific therapies, as demonstrated by the synergistic inhibition of cell proliferation in KRAS G12C-mutant cell lines when treated with MRTX849/AMG510 and KPT9274. Evidence Type: Oncogenic | Mutation: G12C | Summary: The KRAS G12C mutation contributes to tumor development and progression, as indicated by its presence in various cancer cell lines and the observed effects of targeted therapies.

Gene→Variant (gene-first): 3845:G12C

Genes: 3845

Variants: G12C

[Paper-level Aggregated] PMCID: PMC1240052

Evidence Type(s): Functional

Summary: Mutation: D837A | Summary: The D837A mutation is described as kinase-dead and kinase-inactive, failing to induce colony formation, indicating an alteration in molecular function compared to the wild-type EGFR.

Evidence Type: Functional Mutation: L858R | Summary: The L858R mutation in EGFR is associated with ligand-independent autophosphorylation, constitutive phosphorylation of Shc, and constitutive activation of STAT signaling pathways, indicating alterations in molecular function related to receptor activation and downstream signaling pathways.

Evidence Type: Functional Mutation: mutant EGFR | Summary: The mutant EGFR leads to constitutive activation of signaling pathways, indicating an alteration in molecular function related to cell survival.

Gene→Variant (gene-first): EGFR(1956):D837A EGFR(1956):L858R NA:mutant EGFR

Genes: EGFR(1956) NA

Variants: D837A L858R mutant EGFR

[Paper-level Aggregated] PMCID: PMC1240052

Evidence Type(s): Oncogenic

Summary: Mutation: G719S | Summary: The G719S mutation contributes to tumor development by transforming NIH-3T3 cells to anchorage independence and promoting tumor formation in immunocompromised mice, indicating its role in altered cellular behavior and tumor progression.

Evidence Type: Oncogenic Mutation: L858R | Summary: The L858R mutation contributes to tumor development and progression by transforming NIH-3T3 cells, enhancing anchorage-independent growth, and activating oncogenic signaling pathways. It has been shown to form tumors in immunocompromised mice and is associated with constitutive activation of downstream signaling pathways.

Evidence Type: Oncogenic Mutation: A750P | Summary: The A750P mutation contributes to tumor development by promoting colony formation in soft agar, indicating its transforming activity.

Evidence Type: Oncogenic Mutation: D770_N771insNPG | Summary: The D770_N771insNPG mutation demonstrates transforming activity, contributing to tumor development as indicated by increased colony formation efficiency in NIH-3T3 cells.

Evidence Type: Oncogenic Mutation: L747_E749del | Summary: The L747_E749del mutation has transforming activity, contributing to tumor development through enhanced colony formation in soft agar.

Evidence Type: Oncogenic Mutation: L747_E749del A750P | Summary: The L747_E749del A750P deletion and insertion mutants formed colonies in soft agar with high efficiency, suggesting their oncogenic potential.

Evidence Type: Oncogenic Mutation: mutant EGFR | Summary: The mutant EGFR contributes to tumor development by activating downstream signaling pathways involved in promoting cell survival.

Gene→Variant (gene-first): EGFR(1956):G719S EGFR(1956):L858R EGFR(1956):A750P EGFR(1956):D770_N771insNPG NA:L747_E749del EGFR(1956):L747_E749del A750P NA:mutant EGFR

Genes: EGFR(1956) NA

Variants: G719S L858R A750P D770_N771insNPG L747_E749del L747_E749del A750P mutant EGFR

[Paper-level Aggregated] PMCID: PMC1240052

Evidence Type(s): Predictive

Summary: Mutation: G719S | Summary: The G719S mutation is associated with resistance to gefitinib, indicating its predictive value for therapy response in lung adenocarcinoma patients.

Evidence Type: Predictive Mutation: L747_E749del A750P | Summary: The L747_E749del A750P mutation correlates with sensitivity to gefitinib and erlotinib, supporting its predictive role in therapy response for lung adenocarcinoma.

Evidence Type: Predictive Mutation: L858R | Summary: The L858R mutation is linked to increased sensitivity to gefitinib and erlotinib, demonstrating its predictive significance for treatment outcomes in lung adenocarcinoma patients. Additionally, it is associated with a response to the irreversible EGFR inhibitor CL-387,785, which shows greater effectiveness compared to gefitinib or erlotinib in inhibiting colony formation and autophosphorylation.

Gene→Variant (gene-first): EGFR(1956):G719S EGFR(1956):L747_E749del A750P EGFR(1956):L858R

Genes: EGFR(1956)

Variants: G719S L747_E749del A750P L858R

[Paper-level Aggregated] PMCID: PMC12221223

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The text describes C>T transitions as characteristic of UV-induced mutations in melanoma, which are well-established features of cutaneous melanoma, indicating a role in tumorigenesis. Predictive: The identification of specific mutations, such as C>T transitions, suggests potential pharmacological targets for treatment in NF1Mut melanomas, indicating a predictive aspect for therapeutic response.

Gene→Variant (gene-first): NF1(4763):C>T

Genes: NF1(4763)

Variants: C>T

[Paper-level Aggregated] PMCID: PMC11551396

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text indicates that the exon 20 insertion variants (insASV and insSVD) exhibit enhanced catalytic rates and lower Km values compared to WT EGFR, suggesting their role in promoting cancer through increased activity. Predictive: The study evaluates the sensitivity of various EGFR mutations, including L858R and exon 20 insertions, to different inhibitors, indicating that the presence of specific mutations can predict the effectiveness of targeted therapies. Functional: The biochemical analysis of the variants, including kinetic studies and enzyme assays, demonstrates their functional characteristics, such as catalytic efficiency and inhibitor sensitivity, which are critical for understanding their role in cancer biology.

Gene→Variant (gene-first): EGFR(1956):C797 EGFR(1956):T790 EGFR(1956):T790M EGFR(1956):V948R TXK(7294):Glu4 EGFR(1956):L858R EGFR(1956):N771insSVD

Genes: EGFR(1956) TXK(7294)

Variants: C797 T790 T790M V948R Glu4 L858R N771insSVD

[Paper-level Aggregated] PMCID: PMC11272140

Evidence Type(s): Oncogenic, Prognostic, Functional

Justification: Oncogenic: The G2032R mutation is associated with acquired resistance to crizotinib and is shown to respond to taletrectinib, indicating its role in cancer progression. Prognostic: The response rates and progression-free survival data for patients with G2032R mutations suggest that this variant can provide prognostic information regarding treatment outcomes with taletrectinib. Functional: The text indicates that taletrectinib has activity against the G2032R mutation, suggesting that this variant has functional implications in the context of treatment response.

Gene→Variant (gene-first): ROS1(6098):G2032R NTRK1(4914):G2101A TXK(7294):L2026M TXK(7294):S1986F

Genes: ROS1(6098) NTRK1(4914) TXK(7294)

Variants: G2032R G2101A L2026M S1986F

[Paper-level Aggregated] PMCID: PMC11253285

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The text discusses the resistance mechanisms in tumor cells and the effects of specific treatments, indicating that the variants S3C and S4D may be involved in oncogenic processes related to PARPi resistance and tumor growth. Functional: The study assesses the functional impact of SRA737 and PARPi on cell growth and signaling pathways, demonstrating how these variants influence the response to treatment and cellular behavior.

Gene→Variant (gene-first): CHEK1(1111):S3C PARP1(142):S4D

Genes: CHEK1(1111) PARP1(142)

Variants: S3C S4D

[Paper-level Aggregated] PMCID: PMC10805385

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The text indicates that HOXC10 is overexpressed in KRAS-mutant tumors, specifically mentioning the KRAS G12C variant, which is known to be associated with oncogenic activity in cancer. Predictive: The mention of robust HOXC10 expression in a patient-derived xenograft model with the KRAS G12C variant suggests that HOXC10 expression may predict response to treatment with MEK/BET inhibitors, indicating its potential as a predictive biomarker.

Gene→Variant (gene-first): KRAS(3845):G12C TP53(7157):G245V

Genes: KRAS(3845) TP53(7157)

Variants: G12C G245V

[Paper-level Aggregated] PMCID: PMC10690049

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text discusses the KRAS G12C and G12D mutations in the context of cancer cell lines, indicating that these variants are associated with tumorigenic properties, particularly highlighting the specific response of KRASG12C to treatment. Predictive: The evidence suggests that the presence of the KRAS G12C mutation predicts a positive response to the drug combination of MRTX849 and KPT9274, as indicated by the synergistic growth inhibition observed in KRASG12C-mutant cell lines. Functional: The study demonstrates the functional impact of KRAS G12C and G12D mutations on cell growth and drug response, showing that KRASG12C-mutant cells are sensitive to specific inhibitors while KRASG12D-mutant cells are not.

Gene→Variant (gene-first): KRAS(3845):G12C KRAS(3845):G12D

Genes: KRAS(3845)

Variants: G12C G12D

[Paper-level Aggregated] PMCID: PMC10618648

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The ERBB2 mutations V777L and G778A were identified in the tyrosine kinase domain, indicating their potential role in tumorigenesis. Functional: The T733I mutation was noted to be weakly transforming and associated with resistance to lapatinib, suggesting a functional impact on the behavior of the cancer cells.

Gene→Variant (gene-first): ERBB2(2064):G778A ERBB2(2064):V777L ERBB2(2064):T733I

Genes: ERBB2(2064)

Variants: G778A V777L T733I

[Paper-level Aggregated] PMCID: PMC10527017

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

Justification: Oncogenic: The HER2V777L and PIK3CAH1047R mutations are described as activating mutations that promote tumor formation and aggressive cancer characteristics, indicating their role in oncogenesis. Functional: The study demonstrates that the combination of HER2V777L and PIK3CAH1047R mutations enhances cellular migration and invasion, which are functional properties associated with metastatic cancer. Predictive: The findings suggest that the presence of HER2V777L and PIK3CAH1047R mutations can predict the effectiveness of specific drug combinations, such as neratinib plus trastuzumab deruxtecan, in treating breast cancer. Prognostic: The study indicates that the co-occurrence of HER2 and PIK3CA mutations is associated with accelerated tumor growth and metastasis, which can serve as a prognostic indicator for disease progression in breast cancer patients.

Gene→Variant (gene-first): ERBB2(2064):G776insYVMA ERBB2(2064):V777L PIK3CA(5290):H1047R

Genes: ERBB2(2064) PIK3CA(5290)

Variants: G776insYVMA V777L H1047R

[Paper-level Aggregated] PMCID: PMC10524391

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

Justification: Oncogenic: The presence of mutations such as EGFR T790M, L858R, and RET G810S is associated with resistance to targeted therapies, indicating their role in tumor progression and oncogenic potential. Predictive: The identification of specific mutations like EGFR T790M and RET G810S can predict resistance to therapies such as osimertinib, guiding treatment decisions. Functional: The text discusses resistance mutations that affect the function of EGFR and RET kinases, indicating their functional impact on therapeutic engagement and resistance mechanisms. Prognostic: The presence of mutations such as BRAF V600E and KRAS G12S, along with the response rates to treatment, suggests that these mutations may have prognostic implications for patient outcomes.

Gene→Variant (gene-first): EGFR(1956):C797S KRAS(3845):G12S RET(5979):G810S EGFR(1956):T790M BRAF(673):V600E RET(5979):V804E RET(5979):V804M RET(5979):V804M/E EGFR(1956):L747S EGFR(1956):L858R

Genes: EGFR(1956) KRAS(3845) RET(5979) BRAF(673)

Variants: C797S G12S G810S T790M V600E V804E V804M V804M/E L747S L858R

[Paper-level Aggregated] PMCID: PMC10390864

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

Justification: Functional: The study assessed the influence of various RAD51C missense mutations on HDR DNA repair activity, categorizing them as deleterious, hypomorphic, or neutral based on their effects on HDR scores, indicating their functional impact on DNA repair mechanisms. Oncogenic: The loss of RAD51C function promotes HR deficiency and sensitizes cells to cisplatin and olaparib, suggesting that variants affecting RAD51C function may contribute to oncogenic processes by impairing DNA repair and influencing drug sensitivity in cancer cells. Predictive: The study evaluated the sensitivity of cells with different RAD51C variants to cisplatin and olaparib, indicating that specific variants can predict responses to these drugs, which is crucial for therapeutic decision-making in cancer treatment. Prognostic: The correlation between RAD51C variant status and drug response (IC50 values) suggests that these variants may serve as prognostic markers for treatment outcomes in patients receiving cisplatin or olaparib.

Gene→Variant (gene-first): RAD51C(5889):16 A RAD51C(5889):C135Y RAD51C(5889):E94K RAD51C(5889):G130R RAD51C(5889):G302V RAD51C(5889):K131 RAD51C(5889):L138F RAD51C(5889):P21S RAD51C(5889):Q133E RAD51C(5889):R168 RAD51C(5889):R168G RAD51C(5889):R312 RAD51C(5889):R312W RAD51C(5889):T132I RAD51C(5889):T132R RAD51D(5892):T86I RAD51C(5889):V140E RAD51C(5889):p.Cys135Tyr RAD51C(5889):p.Thr132Ile RAD51C(5889):p.Val140Glu RAD51C(5889):A126T RAD51C(5889):D159N RAD51C(5889):G125V RAD51C(5889):G153D RAD51C(5889):G264S RAD51C(5889):G264V RAD51C(5889):G3R RAD51C(5889):L219S RAD51C(5889):Q143R RAD51C(5889):R214C RAD51C(5889):R258H RAD51C(5889):R366Q RAD51C(5889):T287A RAD51C(5889):V169A RAD51C(5889):p.Arg214Cys RAD51C(5889):p.Arg258His RAD51C(5889):p.Arg312Trp RAD51C(5889):p.Arg366Gln RAD51C(5889):p.Asp159Asn RAD51C(5889):p.Gln143Arg RAD51C(5889):p.Gly125Val RAD51C(5889):p.Gly153Asp RAD51C(5889):p.Gly264Ser RAD51C(5889):p.Gly264Val RAD51C(5889):p.Gly3Arg RAD51C(5889):p.Leu219Ser RAD51C(5889):p.Thr287Ala RAD51C(5889):p.Val169Ala RAD51C(5889):D109Y RAD51C(5889):G162E RAD51C(5889):L27P RAD51C(5889):S163R RAD51C(5889):T336P RAD51C(5889):p.Gly162Glu RAD51C(5889):p.Ser163Arg RAD51C(5889):p.Thr336Pro RAD51D(5892):p.Thr86Ile RAD51C(5889):A155E RAD51C(5889):C147Y RAD51(5888):D108G RAD51C(5889):D159Y RAD51C(5889):G306R RAD51C(5889):p.Ala155Glu RAD51(5888):p.Asp108Gly RAD51C(5889):p.Asp109Tyr RAD51C(5889):p.Asp159Tyr RAD51C(5889):p.Cys147Tyr RAD51C(5889):p.Gly306Arg RAD51C(5889):p.Pro21Ser RAD51C(5889):p.Glu94Lys RAD51C(5889):K131I

Genes: RAD51C(5889) RAD51D(5892) RAD51(5888)

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 A126T D159N G125V G153D G264S G264V G3R L219S Q143R R214C R258H 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 D109Y G162E L27P S163R T336P p.Gly162Glu p.Ser163Arg p.Thr336Pro p.Thr86Ile A155E C147Y D108G D159Y G306R p.Ala155Glu p.Asp108Gly p.Asp109Tyr p.Asp159Tyr p.Cys147Tyr p.Gly306Arg p.Pro21Ser p.Glu94Lys K131I

[Paper-level Aggregated] PMCID: PMC10283448

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The presence of the ROS1-G2032R mutation is associated with crizotinib resistance in lung cancer, indicating its role in tumor progression and treatment failure. Functional: The study investigates the functional impact of various mutations, including E253Q, H178Q, H179Y, H555R, R143Q, and E171G, in the context of acquired resistance to repotrectinib, suggesting their potential roles in tumor biology and treatment response.

Gene→Variant (gene-first): CEBPA(1050):196_197insHP TP53(7157):E171G CCND3(896):E253Q ERBB2(2064):H178Q TP53(7157):H179Y RB1(5925):H555R ERBB2(2064):R143Q ROS1(6098):G2032R

Genes: CEBPA(1050) TP53(7157) CCND3(896) ERBB2(2064) RB1(5925) ROS1(6098)

Variants: 196_197insHP E171G E253Q H178Q H179Y H555R R143Q G2032R

[Paper-level Aggregated] PMCID: PMC10183391

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text describes a patient with stage IV NSCLC harboring the HER2 exon 19 p.L755P mutation, which is associated with the disease and indicates a potential role in tumorigenesis. Predictive: The evidence suggests that the presence of the HER2 exon 19 p.L755P mutation may predict the efficacy of osimertinib treatment, as the patient achieved a partial response after treatment. Functional: The text indicates that osimertinib has demonstrated activity against the HER2 exon 19 p.L755P mutation in both pre-clinical studies and in the reported case, suggesting a functional impact of the mutation on treatment response.

Gene→Variant (gene-first): ERBB2(2064):c.2262_2264delinsTCC ERBB2(2064):p.(L755P) ERBB2(2064):p.L755P

Genes: ERBB2(2064)

Variants: c.2262_2264delinsTCC p.(L755P) p.L755P

[Paper-level Aggregated] PMCID: PMC10161095

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The text describes how lysine-to-methionine mutations in histone H3 at lysine 27 (H3K27M) are associated with lethal childhood brain cancers, indicating that this variant contributes to tumorigenesis. Functional: The evidence shows that H3K27M mutations alter chromatin remodeling and affect protein levels of the SWI/SNF complex, demonstrating a functional impact on cellular processes related to cancer.

Gene→Variant (gene-first): H3-3B(3021):lysine 27 PBRM1(55193):lysine-to-methionine

Genes: H3-3B(3021) PBRM1(55193)

Variants: lysine 27 lysine-to-methionine

[Paper-level Aggregated] PMCID: PMC10082285

Evidence Type(s): Predictive, Prognostic, Oncogenic

Justification: Predictive: The study involves patients with EGFR-mutated NSCLC, specifically mentioning the L858R variant, and evaluates the efficacy of osimertinib, indicating that the presence of this mutation can predict response to treatment. Prognostic: The study assesses disease-free survival (DFS) and overall survival in patients with the L858R variant, suggesting that this mutation may have implications for patient outcomes. Oncogenic: The mention of the L858R mutation in the context of EGFR-mutated NSCLC indicates its role in driving cancer development, classifying it as an oncogenic variant.

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

Genes: EGFR(1956)

Variants: L858R

[Paper-level Aggregated] PMCID: PMC10015977

Evidence Type(s): Prognostic, Oncogenic, Functional

Justification: Prognostic: The text indicates that SF3B1 mutations, particularly K700E, are associated with a favorable prognosis in myelodysplastic syndromes (MDS), as evidenced by superior overall survival (OS) rates compared to SF3B1 wild-type patients. Oncogenic: The presence of SF3B1 mutations, including K700E and R625C, is implicated in the pathogenesis of myelodysplastic syndromes, suggesting their role as oncogenic drivers in this context. Functional: The analysis of splicing events and gene expression profiles between K700E and non-K700E SF3B1 mutations indicates functional differences that may impact disease characteristics and outcomes in MDS.

Gene→Variant (gene-first): SETBP1(26040):E862K SF3B1(23451):K700E SF3B1(23451):R625C SF3B1(23451):K666 SF3B1(23451):K700 SF3B1(23451):R625

Genes: SETBP1(26040) SF3B1(23451)

Variants: E862K K700E R625C K666 K700 R625

[Paper-level Aggregated] PMCID: PMC10011885

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The BRAF V600E mutation is identified as a significant alteration in metastatic colorectal cancer (mCRC) and is associated with the disease's progression and treatment resistance, indicating its role in oncogenesis. Predictive: Early ctDNA dynamics, including changes in BRAF V600E levels, were shown to predict treatment efficacy, with significant correlations between ctDNA levels and clinical outcomes such as progression-free survival (PFS) and overall survival (OS). Functional: The emergence of KRAS and NRAS mutations, including specific variants like KRAS Q61H and G13D, was linked to treatment resistance, suggesting that these mutations have functional implications in the context of therapy response.

Gene→Variant (gene-first): KDR(3791):A163G KRAS(3845):G12D KRAS(3845):G12N KRAS(3845):G13D KRAS(3845):Q61H NRAS(4893):Q61L SLTM(79811):R106H BRAF(673):V600E NRAS(4893):G13C

Genes: KDR(3791) KRAS(3845) NRAS(4893) SLTM(79811) BRAF(673)

Variants: A163G G12D G12N G13D Q61H Q61L R106H V600E G13C

[Paper-level Aggregated] PMCID: PMC9900321

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The passage indicates that Gly-to-Asp mutations (KRASG12D) are commonly found in pancreatic ductal adenocarcinoma (PDAC), suggesting that this variant is associated with the development of cancer. Predictive: The text discusses the efficacy of a small-molecule KRASG12D inhibitor, MRTX1133, in models with KRASG12D mutations, indicating that the presence of this variant can predict the response to targeted therapy.

Gene→Variant (gene-first): KRAS(3845):Gly-to-Asp

Genes: KRAS(3845)

Variants: Gly-to-Asp

[Paper-level Aggregated] PMCID: PMC9859631

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The text describes various ERBB2 alterations, including ERBB2DeltaEx16 variants, which are suggested to play a role in resistance to targeted therapies, indicating their potential oncogenic nature. Predictive: The presence of specific mutations such as L858R, L755S, D769Y, and others in the context of treatment resistance suggests that these variants may predict response to therapies and disease progression. Functional: The identification of multiple ERBB2 alterations and their association with resistance mechanisms implies that these variants may have functional consequences on the gene's activity and its role in cancer progression.

Gene→Variant (gene-first): SLTM(79811):D1288N L1195I SLTM(79811):L1195V SLTM(79811):Y1230H ERBB2(2064):c.1899-936_1946+520del ERBB2(2064):D769Y ERBB2(2064):L755S EGFR(1956):L858R ERBB2(2064):c.1899-32_1909del ERBB2(2064):c.1899-2A>G ERBB2(2064):c.1899-880_1946+761del

Genes: SLTM(79811) ERBB2(2064) EGFR(1956)

Variants: D1288N L1195I L1195V Y1230H c.1899-936_1946+520del D769Y L755S L858R c.1899-32_1909del c.1899-2A>G c.1899-880_1946+761del

[Paper-level Aggregated] PMCID: PMC9837058

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The text discusses multiple mutations (e.g., H1047R, G1049R, M1043L, N1068fs) that are frequently observed in cancer and describes their role in activating the PI3K pathway, indicating their oncogenic potential. Functional: The evidence describes how specific mutations (H1047R, G1049R, M1043L) lead to increased ATPase activity and enhanced membrane binding, demonstrating their functional impact on the PI3K enzyme activity. Predictive: The identification of specific mutations associated with increased membrane binding and PI3K activity suggests that these mutations could be used to predict the behavior of tumors and their response to therapies targeting the PI3K pathway.

Gene→Variant (gene-first): PIK3CA(5290):D915N PIK3CA(5290):E726K PIK3CA(5290):G1049R PIK3CA(5290):H1047R PIK3CA(5290):H1047R/L PIK3CA(5290):M1043L PIK3CA(5290):M1043L/I PIK3CA(5290):N1044K PIK3CA(5290):N1068fs PIK3CA(5290):M1043I/L PIK3CA(5290):G106V PIK3CA(5290):G118D PIK3CA(5290):N345K PIK3CA(5290):His1047 PIK3CA(5290):Met1043

Genes: PIK3CA(5290)

Variants: D915N E726K G1049R H1047R H1047R/L M1043L M1043L/I N1044K N1068fs M1043I/L G106V G118D N345K His1047 Met1043

[Paper-level Aggregated] PMCID: PMC9468105

Evidence Type(s): Predisposing, Oncogenic, Prognostic

Justification: Predisposing: The text describes gliomas arising in patients with a heterozygous germline mutation in NF1, indicating a genetic predisposition to tumor development. Oncogenic: The presence of somatic mutations and inactivation of the wild-type NF1 allele, along with the mention of specific mutations like p.R1276* and c.4110 + 2 T > G, supports the role of these variants in tumorigenesis. Prognostic: Kaplan-Meier survival analysis indicates that patients with NF1-associated gliomas have inferior outcomes, suggesting that the genetic alterations may have prognostic implications for patient survival.

Gene→Variant (gene-first): NF1(4763):c.4110 + 2 T > G NF1(4763):p.R1276* BRAF(673):p.V600E

Genes: NF1(4763) BRAF(673)

Variants: c.4110 + 2 T > G p.R1276* p.V600E

[Paper-level Aggregated] PMCID: PMC9441062

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of EGFR mutations, including L858R and G719C/S768I, is associated with oncogenic activity in NSCLC, as they are known to drive tumorigenesis. Predictive: The identified second-site EGFR mutations, such as T790M and C797S/G, are recognized as predictive markers for resistance to EGFR-TKIs, indicating their role in treatment response. Prognostic: The study reports that certain genetic alterations, including bypass pathway mutations and co-mutations of TP53 and RB1, are associated with significantly shorter progression-free survival (PFS) in patients treated with EGFR-TKIs, highlighting their prognostic significance.

Gene→Variant (gene-first): EGFR(1956):C797S/G EGFR(1956):L718V/Q EGFR(1956):T790M EGFR(1956):G719C EGFR(1956):L858R EGFR(1956):S768I

Genes: EGFR(1956)

Variants: C797S/G L718V/Q T790M G719C L858R S768I

[Paper-level Aggregated] PMCID: PMC9402235

Evidence Type(s): Oncogenic, Diagnostic, Predictive

Justification: Oncogenic: The de novo pathogenic variant NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) is associated with VHL-independent renal tumorigenesis and has been previously described as a somatic variant in renal cell carcinomas (RCCs) without VHL inactivation, indicating its role in cancer development. Diagnostic: The identification of the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant in a proband with VHL disease suggests that genetic testing for ELOC variants should be performed in individuals with suspected VHL disease, thereby aiding in diagnosis. Predictive: The presence of the NM_005648.4(ELOC):c.236A>G (p.Tyr79Cys) variant has implications for predicting the development of VHL disease and associated renal tumors, as it mimics the effects of pVHL deficiency on hypoxic signaling.

Gene→Variant (gene-first): HIF1A(3091):Tyr79 HIF1A(3091):Y79 HIF1A(3091):c.236A>G HIF1A(3091):p.Tyr79Cys ELOC(6921):c.261_272del RET(5979):c.274G>A ELOC(6921):c.311T>A KRT7(3855):c.74A>T KRT7(3855):p.Asp25Val VAV1(7409):p.Glu92Lys ELOC(6921):p.Leu104Gln ELOC(6921):p.Thr88_Pro91del

Genes: HIF1A(3091) ELOC(6921) RET(5979) KRT7(3855) VAV1(7409)

Variants: Tyr79 Y79 c.236A>G p.Tyr79Cys c.261_272del c.274G>A c.311T>A c.74A>T p.Asp25Val p.Glu92Lys p.Leu104Gln p.Thr88_Pro91del

[Paper-level Aggregated] PMCID: PMC9398166

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

Justification: Oncogenic: The text discusses various ALK mutations, including G1202R and L1196M, which are described as major resistance mechanisms to ALK inhibitors, indicating their role in oncogenesis. Functional: The evidence describes the biochemical characterization of TPX-0131's potency against various ALK mutations, demonstrating its functional ability to inhibit both wild-type and mutant ALK, including resistance mutations. Predictive: The text indicates that TPX-0131 was designed to avoid resistance mutations and shows significant potency against them, suggesting its potential predictive value for treatment outcomes in patients with these mutations. Prognostic: The discussion of TPX-0131's efficacy against a range of ALK mutations, including those associated with resistance, implies that the presence of these mutations could influence treatment response and patient prognosis.

Gene→Variant (gene-first): ALK(238):C1156Y ALK(238):D1203N ALK(238):E1210K ALK(238):F1174C ALK(238):F1174L ALK(238):F1174S ALK(238):F1245C ALK(238):G1202 ALK(238):G1202R ALK(238):G1269A ALK(238):G1269S ALK(238):I1171N ALK(238):L1152P ALK(238):L1152R ALK(238):L1196M ALK(238):L1198F ALK(238):R1275Q ALK(238):S1206C ALK(238):S1206R ALK(238):T1151-L1152 insT ALK(238):T1151M ALK(238):V1180L ALK(238):I1171N/S ALK(238):L1204V ALK(238):S/T ALK(238):L1198

Genes: ALK(238)

Variants: C1156Y D1203N E1210K F1174C F1174L F1174S F1245C G1202 G1202R G1269A G1269S I1171N L1152P L1152R L1196M L1198F R1275Q S1206C S1206R T1151-L1152 insT T1151M V1180L I1171N/S L1204V S/T L1198

[Paper-level Aggregated] PMCID: PMC9365372

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The text indicates that patients with the EGFR T790M mutation showed responses to treatment with abivertinib, suggesting that the presence of this variant can predict treatment efficacy. Oncogenic: The T790M variant is associated with resistance to EGFR inhibitors and is implicated in the progression of non-small cell lung cancer (NSCLC), indicating its role in oncogenesis.

Gene→Variant (gene-first): EGFR(1956):T790M EGFR(1956):Thr790Met

Genes: EGFR(1956)

Variants: T790M Thr790Met

[Paper-level Aggregated] PMCID: PMC9338780

Evidence Type(s): Predictive, Oncogenic, Prognostic

Justification: Predictive: The text discusses the approval of dabrafenib plus trametinib for treatment of BRAF V600E-mutant anaplastic thyroid cancer, indicating that the presence of the V600E mutation predicts a positive response to this therapy. Oncogenic: The BRAF V600E mutation is implicated in the pathogenesis of anaplastic thyroid cancer, suggesting its role as an oncogenic driver in this disease. Prognostic: The updated results indicate that patients with BRAF V600E-mutant ATC experienced improved long-term survival with the treatment, suggesting that the mutation may serve as a prognostic marker for treatment outcomes.

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

Genes: BRAF(673)

Variants: V600E

[Paper-level Aggregated] PMCID: PMC8887939

Evidence Type(s): Prognostic, Oncogenic

Justification: Prognostic: The text provides data on overall response rates (ORR), median duration of response (DoR), and median progression-free survival (PFS) associated with specific mutations, indicating their potential to predict clinical outcomes. Oncogenic: The mention of specific mutations (A775dupYVMA and G776delinsVC) in the context of their frequency and associated clinical outcomes suggests a role in tumorigenesis.

Gene→Variant (gene-first): ERBB2(2064):A775dupYVMA ERBB2(2064):G776delinsVC

Genes: ERBB2(2064)

Variants: A775dupYVMA G776delinsVC

[Paper-level Aggregated] PMCID: PMC8881279

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The evidence indicates that the ERBB2 E401G variant enhances C-terminal phosphorylation and increases invasive capacity in cancer cells, suggesting its role in promoting oncogenic properties. Functional: The study demonstrates that ERBB2 E401G has functional properties similar to known activating mutations, affecting dimerization and phosphorylation mechanisms, which are critical for its role in signaling pathways. Predictive: The identification of the ERBB2 E401G variant as a variant of unknown significance (VUS) and its evaluation through computational tools predicting pathogenicity suggest its potential as a predictive marker for therapeutic targeting.

Gene→Variant (gene-first): MYC(4609):1157A > G FANCC(2176):E401G ERBB2(2064):D845A TP53(7157):E321G ERBB2(2064):S310F FANCC(2176):p.(E401G)

Genes: MYC(4609) FANCC(2176) ERBB2(2064) TP53(7157)

Variants: 1157A > G E401G D845A E321G S310F p.(E401G)

[Paper-level Aggregated] PMCID: PMC8727519

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of the EGFR L858R and T790M variants in the patient's lung adenocarcinoma indicates their role in tumorigenesis and resistance to treatment, supporting their classification as oncogenic. Predictive: The identification of the T790M variant suggests a potential resistance mechanism to first-generation EGFR tyrosine kinase inhibitors, indicating its predictive value for treatment response. Prognostic: The patient's progression-free survival interval of more than 11 months after switching to osimertinib suggests that the presence of the T790M variant may have prognostic implications for treatment outcomes in NSCLC.

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

Genes: EGFR(1956)

Variants: L858R T790M

[Paper-level Aggregated] PMCID: PMC8700411

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The text describes EGFR exon 20 insertion mutations, including G770 equivalence, as being associated with sensitivity to specific EGFR TKIs, indicating their role in driving cancer progression. Predictive: The evidence suggests that patients with EGFR exon 20 insertion mutations, particularly those with G770 equivalence, can be predicted to respond to certain EGFR TKIs, such as afatinib and dacomitinib, based on preclinical and clinical data. Prognostic: The clinical outcomes reported for patients with EGFR exon 20 insertion mutations indicate that these mutations can influence treatment responses and outcomes, suggesting a prognostic role in advanced lung cancers.

Gene→Variant (gene-first): EGFR(1956):D770 EGFR(1956):G770 EGFR(1956):Y764insFQEA EGFR(1956):D770_N771insSVD EGFR(1956):V769dupASV

Genes: EGFR(1956)

Variants: D770 G770 Y764insFQEA D770_N771insSVD V769dupASV

[Paper-level Aggregated] PMCID: PMC8688876

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

Justification: Functional: The text discusses the biochemical properties of KRAS variants, including their effects on GTP binding, hydrolysis rates, and RAF affinity, indicating that these variants have functional consequences on the protein's activity. Oncogenic: The mention of KRAS variants, particularly hotspot mutations, in the context of their roles in cancer suggests that these mutations are associated with oncogenic potential, as they alter the protein's function in a way that can contribute to tumorigenesis. Predictive: The analysis includes predictions of RAF affinity and GAP-mediated hydrolysis rates for various KRAS variants, indicating that the data can be used to predict the functional impact of these mutations on KRAS activity. Prognostic: The study's findings on the varying effects of different KRAS mutations on downstream signaling and their correlation with pERK levels suggest that these variants may have prognostic implications in cancer outcomes.

Gene→Variant (gene-first): KRAS(3845):A146T KRAS(3845):A146T/V HRAS(3265):A59T KRAS(3845):G12A/R KRAS(3845):G12A/R/S KRAS(3845):G12V/D KRAS(3845):G13C KRAS(3845):G13V/D BRAF(673):K177N KRAS(3845):L19F KRAS(3845):Q22K KRAS(3845):Q61 KRAS(3845):Q61H KRAS(3845):Q61L/P KRAS(3845):R164Q ZHX2(22882):T74P HRAS(3265):A146V BRAF(673):A18D KRAS(3845):G12D KRAS(3845):G12S KRAS(3845):G13D HRAS(3265):G13V KRAS(3845):K117N KRAS(3845):G12C KRAS(3845):G12C/D KRAS(3845):G12R KRAS(3845):G13C/D KRAS(3845):Q61H/L KRAS(3845):Q61P NRAS(4893):Q61R ZHX2(22882):V/A KRAS(3845):G12 KRAS(3845):G13 KRAS(3845):G12V ZHX2(22882):T74

Genes: KRAS(3845) HRAS(3265) BRAF(673) ZHX2(22882) NRAS(4893)

Variants: A146T A146T/V A59T G12A/R G12A/R/S G12V/D G13C G13V/D K177N L19F Q22K Q61 Q61H Q61L/P R164Q T74P A146V A18D G12D G12S G13D G13V K117N G12C G12C/D G12R G13C/D Q61H/L Q61P Q61R V/A G12 G13 G12V T74

[Paper-level Aggregated] PMCID: PMC8453302

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The G292R variant in HER2 is associated with a complete response to treatment, indicating its role in driving cancer progression and treatment response in metastatic cervical adenocarcinoma. Prognostic: The mention of a progression-free survival of 25 months in a patient with the G292R variant suggests that this variant may have implications for predicting treatment outcomes in cervical cancer.

Gene→Variant (gene-first): ERBB2(2064):G292R

Genes: ERBB2(2064)

Variants: G292R

[Paper-level Aggregated] PMCID: PMC8307492

Evidence Type(s): Predictive, Prognostic, Oncogenic

Justification: Predictive: The text discusses the association of specific EGFR mutations, such as L858R and exon 19 deletions, with overall survival (OS) outcomes in patients treated with first-line EGFR inhibitors, indicating their predictive value for treatment response. Prognostic: The analysis of overall survival (OS) based on different EGFR mutation subclasses, including L858R and uncommon actionable variants, demonstrates their prognostic significance in determining patient outcomes. Oncogenic: The presence of EGFR mutations, including L858R and T790M, is associated with non-small-cell lung cancer (NSCLC), indicating their role in oncogenesis.

Gene→Variant (gene-first): EGFR(1956):G719S EGFR(1956):L858R EGFR(1956):L861Q EGFR(1956):T790M EGFR(1956):L861X

Genes: EGFR(1956)

Variants: G719S L858R L861Q T790M L861X

[Paper-level Aggregated] PMCID: PMC8285406

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The text describes several FGFR mutations, including N546K, K656E, S249C, and others, as oncogenic mutations that exhibit significant transforming activities in various cancers, indicating their role in tumorigenesis. Predictive: The evidence indicates that specific FGFR mutations, such as N549D/K and K650M/N, show different sensitivities to FGFR inhibitors, suggesting that these variants can predict the response to targeted therapies. Prognostic: The text mentions that patients with FGFR mutations and fusions had a higher overall response rate to FGFR TKIs compared to those with amplifications, indicating that these mutations may serve as prognostic markers for treatment outcomes.

Gene→Variant (gene-first): PIK3CA(5290):E542K PIK3CA(5290):E545K PIK3CA(5290):H1047R KRAS(3845):G12V FGFR1(2260):N546K FGFR2(2263):N549D/K FGFR3(2261):G370C FGFR3(2261):G380E/R FGFR3(2261):K650E/M FGFR2(2263):K659E FGFR2(2263):N549H FGFR3(2261):R248C FGFR3(2261):S249C TACC1(6867):S342F FGFR3(2261):S371C FGFR2(2263):W290C FGFR3(2261):Y373C FGFR3(2261):K650E FGFR3(2261):K650M FGFR3(2261):K650N FGFR2(2263):N549K FGFR2(2263):K656 FGFR2(2263):K656E/M FGFR2(2263):N549 FGFR2(2263):N549D/H FGFR1(2260):K656E FGFR2(2263):S252W FGFR2(2263):V550L FGFR4(2264):N535K EGFR(1956):R248H

Genes: PIK3CA(5290) KRAS(3845) FGFR1(2260) FGFR2(2263) FGFR3(2261) TACC1(6867) FGFR4(2264) EGFR(1956)

Variants: E542K E545K H1047R G12V N546K N549D/K G370C G380E/R K650E/M K659E N549H R248C S249C S342F S371C W290C Y373C K650E K650M K650N N549K K656 K656E/M N549 N549D/H K656E S252W V550L N535K R248H

[Paper-level Aggregated] PMCID: PMC8255005

Evidence Type(s): Prognostic, Oncogenic, Functional

Justification: Prognostic: The text states that FLT3 mutations are associated with poor prognosis in acute myeloid leukemia (AML), indicating that the presence of these mutations can provide information about the likely outcome of the disease. Oncogenic: The mention of FLT3 mutations, including D835 and F691L, as common genetic alterations in AML suggests that these variants contribute to the development of cancer. Functional: The text discusses the resistance of FLT3 mutations (specifically F691L and D835Y) to FLT3 inhibitors and the mechanisms by which KX2-391 overcomes this resistance, indicating a functional role of these mutations in drug response.

Gene→Variant (gene-first): FLT3(2322):D835 FLT3(2322):D835Y FLT3(2322):F691 FLT3(2322):F691L

Genes: FLT3(2322)

Variants: D835 D835Y F691 F691L

[Paper-level Aggregated] PMCID: PMC8203843

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The IDH1 R132H mutation is associated with glioma and is known to induce homologous recombination defects, which contributes to the oncogenic process in these tumors. Predictive: The study demonstrates that the presence of the IDH1 R132H mutation influences sensitivity to PARP inhibitors, indicating that this variant can predict treatment response in glioma patients.

Gene→Variant (gene-first): IDH1(3417):R132H

Genes: IDH1(3417)

Variants: R132H

[Paper-level Aggregated] PMCID: PMC8078423

Evidence Type(s): Predictive, Oncogenic

Justification: Predictive: The study evaluates the efficacy of encorafenib plus cetuximab in patients with BRAFV600E-mutant metastatic colorectal cancer, indicating that the presence of the BRAFV600E variant predicts a response to this treatment regimen. Oncogenic: The mention of BRAFV600E as a mutation in metastatic colorectal cancer suggests that it plays a role in the oncogenesis of this cancer type, as it is a known driver mutation associated with tumor development.

Gene→Variant (gene-first): BRAF(673):BRAFV600E BRAF(673):V600E

Genes: BRAF(673)

Variants: BRAFV600E V600E

[Paper-level Aggregated] PMCID: PMC8077124

Evidence Type(s): Oncogenic, Functional, Prognostic

Justification: Oncogenic: The FGFR1 p.K656E mutation is described as a known hotspot mutation that is both activating and transforming, indicating its role in tumorigenesis. Functional: The FGFR1 p.V561M mutation is characterized as a gatekeeper mutation that imparts resistance to FGFR inhibitors, suggesting a functional impact on treatment response. Prognostic: The text mentions that pilomyxoid astrocytomas are characterized by shorter survival and high recurrence rates, indicating that the presence of these mutations may have implications for patient prognosis.

Gene→Variant (gene-first): FGFR1(2260):c.1681G>A FGFR1(2260):c.1966A>G FGFR1(2260):p.K656E FGFR1(2260):p.V561M IDH1(3417):p.R132H BRAF(673):p.V600E

Genes: FGFR1(2260) IDH1(3417) BRAF(673)

Variants: c.1681G>A c.1966A>G p.K656E p.V561M p.R132H p.V600E

[Paper-level Aggregated] PMCID: PMC8040738

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of the BRAF p.T599dup mutation in the tumor is associated with tumor growth and progression, indicating its role in oncogenesis. Predictive: The identification of BRAF alterations, including p.T599dup, may assist clinicians in determining alternative targeted treatment strategies, suggesting its predictive value for treatment response. Prognostic: The report discusses the poor prognosis associated with many central nervous system diagnoses, indicating that BRAF mutations may have implications for patient outcomes.

Gene→Variant (gene-first): BRAF(673):V600E BRAF(673):p.T599dup BRAF(673):p.V600E NA:p.T599dup BRAF

Genes: BRAF(673) NA

Variants: V600E p.T599dup p.V600E p.T599dup BRAF

[Paper-level Aggregated] PMCID: PMC8033310

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of PIK3CA mutations (E545K and H1047R) in TNBC cell lines was associated with increased cell proliferation and decreased apoptosis, indicating that these mutations contribute to tumorigenesis. Predictive: The study suggests that PIK3CA mutations may alter the sensitivity of TNBC cells to chemotherapy, as cells with these mutations showed decreased sensitivity to epirubicin treatment. Prognostic: The frequency of PIK3CA mutations in patients with TNBC and their association with clinical outcomes, such as chemotherapy response and recurrence, indicates that these mutations may have prognostic implications for patient outcomes.

Gene→Variant (gene-first): PIK3CA(5290):E545K PIK3CA(5290):H1047R

Genes: PIK3CA(5290)

Variants: E545K H1047R

[Paper-level Aggregated] PMCID: PMC8008494

Evidence Type(s): Functional, Oncogenic, Predictive

Justification: Functional: The text describes a functional assay (HDR) that evaluates the impact of various variants on protein function, indicating that certain variants resulted in loss of function or maintained functionality based on their HDR scores. Oncogenic: The mention of variants being associated with probabilities of pathogenicity >0.99 suggests that these variants may contribute to cancer development, indicating their potential oncogenic nature. Predictive: The text discusses the ability of certain variants to influence sensitivity to PARP inhibitors, which can be used to predict treatment responses in BRCA2-deficient cell lines.

Gene→Variant (gene-first): NA:2619 from Trp to Gly BRCA2(675):2723 from Asp to Asn APRT(353):7522G>A APRT(353):7807G>T APRT(353):7874G>A APRT(353):7879A>G NA:Leu3180 APRT(353):Phe/Asn APRT(353):c.7522G>C BRCA2(675):c.7880T>A BRCA2(675):c.9370A>C BRCA2(675):c.9371A>T BRCA2(675):c.9539T>C BRCA2(675):p.Ala2603Ser BRCA2(675):p.Arg2625Lys BRCA2(675):p.Asn3124His APRT(353):p.Gly2508Arg BRCA2(675):p.Gly2508Ser BRCA2(675):p.Ile2627Val BRCA2(675):c.8723T>G BRCA2(675):c.8905G>A BRCA2(675):p.Val2908Gly BRCA2(675):p.Val2969Met

Genes: NA BRCA2(675) APRT(353)

Variants: 2619 from Trp to Gly 2723 from Asp to Asn 7522G>A 7807G>T 7874G>A 7879A>G Leu3180 Phe/Asn c.7522G>C c.7880T>A c.9370A>C c.9371A>T c.9539T>C p.Ala2603Ser p.Arg2625Lys p.Asn3124His p.Gly2508Arg p.Gly2508Ser p.Ile2627Val c.8723T>G c.8905G>A p.Val2908Gly p.Val2969Met

[Paper-level Aggregated] PMCID: PMC7820803

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The study demonstrates that the p.Ala636Pro variant leads to a significant loss of MSH2 function, as evidenced by the inability of cells expressing this variant to restore sensitivity to 6-thioguanine, indicating a functional impairment in mismatch repair. Oncogenic: The p.Ala636Pro variant is described as a pathogenic founder allele, suggesting its role in contributing to cancer predisposition, particularly in the context of MMR deficiency associated with Lynch syndrome.

Gene→Variant (gene-first): MSH2(4436):p.Ala636Pro

Genes: MSH2(4436)

Variants: p.Ala636Pro

[Paper-level Aggregated] PMCID: PMC7785563

Evidence Type(s): Oncogenic, Predisposing

Justification: Oncogenic: The text indicates that 90% of the cases harbored the IDH1-R132H mutation, which is associated with conventional supratentorial IDH-mutant astrocytomas, suggesting its role in tumorigenesis. Predisposing: The mention of a personal and family history of colorectal cancer in case no. 10, along with the identification of germline mutations in MMR genes, suggests a predisposition to cancer in these cases.

Gene→Variant (gene-first): IDH1(3417):R132H

Genes: IDH1(3417)

Variants: R132H

[Paper-level Aggregated] PMCID: PMC7612475

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The SF3B1K700E mutation is associated with a BRCA-like cellular phenotype that compromises homologous recombination (HR) and increases sensitivity to DNA damaging agents, indicating its role in cancer development. Functional: The SF3B1K700E mutation affects the ability of cells to resolve recombination intermediates and induces unscheduled R-loops, leading to stalled replication forks and reduced replication fork protection, demonstrating a functional impact on DNA repair mechanisms. Predictive: The presence of the SF3B1K700E mutation predicts increased sensitivity to PARP inhibitors and other chemotherapeutic agents, suggesting its potential as a therapeutic target in cancer treatment.

Gene→Variant (gene-first): RNASEH1(246243):D210N SF3B1(23451):K700E

Genes: RNASEH1(246243) SF3B1(23451)

Variants: D210N K700E

[Paper-level Aggregated] PMCID: PMC7612117

Evidence Type(s): Oncogenic, Functional, Predisposing

Justification: Oncogenic: The evidence indicates that the BRCA1 p.L1363P variant disrupts the interaction with PALB2, leads to embryonic lethality, and accelerates the development of Trp53-deficient mammary tumors, suggesting its role in cancer development. Functional: The study demonstrates that Brca1 p.L1363P impairs homologous recombination repair (HRR) and affects BRCA1-PALB2 interaction, indicating a functional defect associated with this variant. Predisposing: The findings suggest that the BRCA1 p.L1363P variant increases the risk of developing breast cancer, as it leads to tumor formation in a mouse model.

Gene→Variant (gene-first): BRCA1(672):4220T>C TP53BP1(7158):p.L1363P BRCA1(672):p.L1407P TP53BP1(7158):L1363P BRCA1(672):leucine to proline

Genes: BRCA1(672) TP53BP1(7158)

Variants: 4220T>C p.L1363P p.L1407P L1363P leucine to proline

[Paper-level Aggregated] PMCID: PMC7611203

Evidence Type(s): Oncogenic, Predictive, Predisposing

Justification: Oncogenic: The text discusses multiple pathogenic mutations, including BRCA1 and BRCA2 variants, which are known to be associated with an increased risk of breast and ovarian cancer, indicating their oncogenic potential. Predictive: The mention of neoantigens derived from pathogenic mutations being likely presented by HLA class I complexes suggests that these mutations can be used to predict immune responses, which is a predictive aspect in the context of cancer treatment. Predisposing: The identification of common founder mutations such as BRCA1:c.185delAG and BRCA2:c.6174delT indicates that these variants predispose individuals to developing certain cancers, thus classifying them as predisposing mutations.

Gene→Variant (gene-first): BRCA1(672):c.185delAG BRCA1(672):c.5266dupC BRCA2(675):c.5946delT BRCA2(675):c.6174delT BRCA1(672):c.68_69delAG BRCA1(672):p.C61S BRCA1(672):p.M1I

Genes: BRCA1(672) BRCA2(675)

Variants: c.185delAG c.5266dupC c.5946delT c.6174delT c.68_69delAG p.C61S p.M1I

[Paper-level Aggregated] PMCID: PMC7568619

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The L1196Q mutation in ALK was identified as a secondary mutation associated with resistance to alectinib, indicating its role in tumor progression and treatment failure. Predictive: The identification of the L1196Q mutation guided the treatment decision to prescribe ceritinib, which resulted in a partial response, suggesting its predictive value for treatment outcomes.

Gene→Variant (gene-first): ALK(238):L1196Q

Genes: ALK(238)

Variants: L1196Q

[Paper-level Aggregated] PMCID: PMC7545690

Evidence Type(s): Prognostic, Predictive

Justification: Prognostic: The variant rs3786362 in TYMS is associated with reduced progression-free survival (PFS) and overall survival (OS) in mCRC patients, indicating its potential as a prognostic marker for patient outcomes. Predictive: The study suggests that rs3786362 may serve as a predictive biomarker for survival in specific subgroups of mCRC patients, as it correlates with treatment response and survival outcomes based on genotype.

Gene→Variant (gene-first): FTCD(10841):rs10432965 FOLH1(2346):rs369803 TYMS(7298):rs3786362 SLC46A1(113235):rs4795436

Genes: FTCD(10841) FOLH1(2346) TYMS(7298) SLC46A1(113235)

Variants: rs10432965 rs369803 rs3786362 rs4795436

[Paper-level Aggregated] PMCID: PMC7499606

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The TP53 Y220C missense mutation is described as a "deleterious somatic mutation," indicating its role in promoting cancer development. Prognostic: The patient's response to various treatments, including the combination therapy, suggests that the presence of the Y220C mutation may influence treatment outcomes and disease progression.

Gene→Variant (gene-first): TP53(7157):Y220C

Genes: TP53(7157)

Variants: Y220C

[Paper-level Aggregated] PMCID: PMC7472556

Evidence Type(s): Oncogenic, Diagnostic, Prognostic

Justification: Oncogenic: The text discusses the upregulation of NRG1 in response to hormone therapy and its association with promoting resistance to androgen deprivation therapy (ADT), indicating a role in cancer progression. Diagnostic: The detection of NRG1 expression using an immunohistochemical assay in patients with localized prostate cancer suggests its potential use as a diagnostic marker for assessing treatment response. Prognostic: The correlation between NRG1 expression and patient outcomes, particularly in relation to ADT treatment, implies that NRG1 levels may serve as a prognostic indicator for treatment efficacy in prostate cancer.

Gene→Variant (gene-first): RET(5979):Q8 NRG1(3084):S6 KAT2B(8850):S7 KAT2B(8850):S7C

Genes: RET(5979) NRG1(3084) KAT2B(8850)

Variants: Q8 S6 S7 S7C

[Paper-level Aggregated] PMCID: PMC7467277

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The text indicates that the genomic segment on chr8:208343-27992852 is associated with somatic copy number alterations (CNA), specifically deletions, which can contribute to tumorigenesis, suggesting an oncogenic role. Functional: The mention of somatic CNAs implies that the alterations may affect gene function, indicating a potential functional impact on the genes located within the specified genomic segment.

Gene→Variant (gene-first): NA:chr8:208343-27992852

Genes: NA

Variants: chr8:208343-27992852

[Paper-level Aggregated] PMCID: PMC7362646

Evidence Type(s): Oncogenic, Prognostic

Justification: Oncogenic: The IDH1 p.R132H mutation is mentioned as a significant alteration in adult gliomas, indicating its role in tumorigenesis. Prognostic: The presence of the IDH1 p.R132H mutation correlates with specific histological grades and patient age cohorts, suggesting it may have implications for patient outcomes.

Gene→Variant (gene-first): IDH1(3417):p.R132H

Genes: IDH1(3417)

Variants: p.R132H

[Paper-level Aggregated] PMCID: PMC7342819

Evidence Type(s): Oncogenic, Predisposing, Functional

Justification: Oncogenic: The presence of the KRAS p.G12V mutation is identified as a common driver mutation in pancreatic cancer, indicating its role in tumorigenesis. Predisposing: The germline mutation PALB2 c.3114-1G>A is noted as likely pathogenic and suggests a potential deficiency in DNA homologous recombination, which can predispose individuals to cancer. Functional: The identification of two deleterious PALB2 alterations, including both a germline and a somatic mutation, suggests functional implications related to DNA repair mechanisms.

Gene→Variant (gene-first): PALB2(79728):c.2514+1G>C PALB2(79728):c.3114-1G>A KRAS(3845):p.G12V

Genes: PALB2(79728) KRAS(3845)

Variants: c.2514+1G>C c.3114-1G>A p.G12V

[Paper-level Aggregated] PMCID: PMC7325368

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The presence of B-RAFV600E and K-RAS mutations is associated with specific responses to treatment, indicating their role in tumorigenesis and cancer progression. Predictive: The study evaluates the efficacy of lifirafenib, a B-RAFV600E inhibitor, suggesting that the presence of this mutation can predict response to the treatment. Prognostic: The outcomes of patients with B-RAF and K-RAS mutations, including response rates and duration of response, provide prognostic information regarding their disease course and treatment efficacy.

Gene→Variant (gene-first): BRAF(673):B-RAFV600E KRAS(3845):G13D

Genes: BRAF(673) KRAS(3845)

Variants: B-RAFV600E G13D

[Paper-level Aggregated] PMCID: PMC7302243

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The presence of the T790M mutation in PC9/GR cells is associated with acquired resistance to EGFR-TKI, indicating its role in promoting cancer cell survival and proliferation despite treatment. Functional: The study demonstrates changes in protein expression and phosphorylation status in cells with the T790M mutation, suggesting that this variant affects cellular signaling pathways and functions related to tumor progression.

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

Genes: EGFR(1956)

Variants: T790M

[Paper-level Aggregated] PMCID: PMC7294133

Evidence Type(s): Oncogenic, Functional, Prognostic

Justification: Oncogenic: The variant EPHB4-V871I is associated with increased proliferation, migration, and invasion properties in neuroblastoma cell lines, indicating its role in promoting tumorigenesis. Functional: The study demonstrates that EPHB4-V871I affects cellular functions such as proliferation and migration, and alters the expression of downstream target genes, confirming its functional impact in vitro. Prognostic: Higher EPHB4 expression, correlated with the EPHB4-V871I variant, is associated with advanced disease stages and poor overall survival in neuroblastoma patients.

Gene→Variant (gene-first): MYCN(4613):A417S EPHB4(2050):V871I ALK(238):F1174L

Genes: MYCN(4613) EPHB4(2050) ALK(238)

Variants: A417S V871I F1174L

[Paper-level Aggregated] PMCID: PMC7293710

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The KRASG12V mutation is associated with increased sensitivity to metformin, indicating its role in promoting tumor growth and response to therapy in colorectal cancer cell lines. Predictive: The presence of the KRASG12V mutation predicts the response of CRC cells to metformin treatment, as evidenced by the differential effects observed in KRAS-mutated versus KRAS wild type cells.

Gene→Variant (gene-first): KRAS(3845):G12V

Genes: KRAS(3845)

Variants: G12V

[Paper-level Aggregated] PMCID: PMC7226056

Evidence Type(s): Prognostic, Oncogenic

Justification: Prognostic: The text discusses the relationship between the expression of RBPs and clinical outcomes in glioma patients, indicating that molecular alterations can predict therapy response and glioma outcomes. Oncogenic: The mention of TERT mutation in gliomas suggests a role in tumorigenesis, as it is associated with different expression patterns of RBPs and the clinical phenotype of gliomas.

Gene→Variant (gene-first): TERT(7015):CGGA 94) in the TCGA

Genes: TERT(7015)

Variants: CGGA 94) in the TCGA

[Paper-level Aggregated] PMCID: PMC7211323

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The text indicates that mutations in the ACVR2A gene, particularly c.1309-1310delAA and c.285delA, are associated with a high mutation frequency and are prevalent in MSI-H gastric cancers, suggesting a role in tumorigenesis. Functional: The in vitro experiments demonstrate that ACVR2A mutations lead to altered protein expression and stability, indicating that these mutations have functional consequences on the gene product. Predictive: The association of ACVR2A mutations with MSI-H status suggests that these mutations could predict the microsatellite instability phenotype in gastric cancer patients.

Gene→Variant (gene-first): ACVR2A(92):1309-1310delAA ACVR2A(92):c.1310delA ACVR2A(92):c.285delA ACVR2A(92):1310AA ACVR2A(92):1310delA ACVR2A(92):c.1309-1310delAA ACVR2A(92):p. D96Tfs*54

Genes: ACVR2A(92)

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

[Paper-level Aggregated] PMCID: PMC7190743

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

Justification: Oncogenic: The text mentions that certain PTEN variants, including C124S and G129E, have been found in somatic cancer, indicating their potential role in cancer development. Functional: The study assesses the functionality of various PTEN variants through multiple assays, demonstrating that many variants exhibit loss of function (LoF) or gain of function (GoF) phenotypes, impacting cellular processes such as synaptogenesis and insulin signaling. Predictive: The classification of variants as Pathogenic or Likely Pathogenic based on their functional impact suggests that these variants can predict disease outcomes, particularly in relation to ASD and other disorders. Predisposing: The identification of variants associated with ASD, intellectual disability, and developmental delay indicates that these genetic alterations may predispose individuals to these conditions.

Gene→Variant (gene-first): PTEN(5728):A126D PTEN(5728):A126P PTEN(5728):C124S PTEN(5728):G129E PTEN(5728):H123Q PTEN(5728):P354Q PTEN(5728):P38H PTEN(5728):Q396R PTEN(5728):R130L PTEN(5728):R130Q PTEN(5728):A79T PTEN(5728):D268E PTEN(5728):G132D PTEN(5728):I101T PTEN(5728):T167N PTEN(5728):Y176C PTEN(5728):C211W PTEN(5728):E157G PTEN(5728):I135V PTEN(5728):I203V PTEN(5728):I400V PTEN(5728):K342N PTEN(5728):K402N PTEN(5728):L345V PTEN(5728):L70V PTEN(5728):M35V PTEN(5728):N117S PTEN(5728):N228S PTEN(5728):N340D PTEN(5728):N340H PTEN(5728):N356D PTEN(5728):Q298E PTEN(5728):S229T PTEN(5728):T202I PTEN(5728):T78A PTEN(5728):W274L PTEN(5728):Y180H PTEN(5728):Y65C PTEN(5728):R130X PTEN(5728):R335X PTEN(5728):Y138L PTEN(5728):H93Y PTEN(5728):R14G PTEN(5728):R15S

Genes: PTEN(5728)

Variants: A126D A126P C124S G129E H123Q P354Q P38H Q396R R130L R130Q A79T D268E G132D I101T T167N Y176C C211W E157G I135V I203V I400V K342N K402N L345V L70V M35V N117S N228S N340D N340H N356D Q298E S229T T202I T78A W274L Y180H Y65C R130X R335X Y138L H93Y R14G R15S

[Paper-level Aggregated] PMCID: PMC7182441

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The text describes the use of alpha-MT to block SLC6A14 function in colon cancer cells, demonstrating that this blockade leads to amino acid starvation and subsequent changes in marker expression, indicating a functional role of SLC6A14 in amino acid nutrition. Oncogenic: The study evaluates the effects of SLC6A14 blockade in a colon cancer cell line (LS174T), suggesting that SLC6A14 may play a role in the oncogenic process by influencing amino acid availability and mTOR signaling in cancer cells.

Gene→Variant (gene-first): RPS6KB1(6198):S6

Genes: RPS6KB1(6198)

Variants: S6

[Paper-level Aggregated] PMCID: PMC7099049

Evidence Type(s): Prognostic, Functional

Justification: Prognostic: The SNPs rs16879870, rs2641256, rs2761591, and rs854936 were significantly associated with HNSCC survival, indicating their potential role in predicting patient outcomes. Functional: The genotypes of rs16879870 and rs854936 were significantly associated with the expression of genes GJB7 and RTN4R, respectively, suggesting a functional impact on gene expression related to HNSCC.

Gene→Variant (gene-first): FGFR4(2264):AUC from 0 NA:rs16879870 SCIMP(388325):rs2641256 DCDC1(341019):rs2761591 NA:rs854936

Genes: FGFR4(2264) NA SCIMP(388325) DCDC1(341019)

Variants: AUC from 0 rs16879870 rs2641256 rs2761591 rs854936

[Paper-level Aggregated] PMCID: PMC7086303

Evidence Type(s): Oncogenic, Predictive

Justification: Oncogenic: The G598V mutation in EGFR is described as an activating mutation that influences the sensitivity of BTSC cultures to afatinib, indicating its role in promoting tumor growth and response to treatment. Predictive: The presence of the G598V mutation is associated with increased sensitivity to afatinib, suggesting that it can predict the effectiveness of this treatment in BTSC cultures.

Gene→Variant (gene-first): EGFR(1956):G598V

Genes: EGFR(1956)

Variants: G598V

[Paper-level Aggregated] PMCID: PMC7081042

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The text indicates that mutations in the HER2 gene, such as S310F, S310Y, R678Q, D769H, and I767M, are associated with favorable outcomes and good responses to anti-HER2 therapy, suggesting their role in cancer progression. Predictive: The mention of specific HER2 mutations (e.g., L755S, D769Y) influencing the efficacy of treatments like neratinib and afatinib indicates their potential as predictive biomarkers for treatment response in HER2-positive breast cancer patients. Prognostic: The text discusses the association of HER2 overexpression with an aggressive phenotype and lower survival rates, indicating that certain mutations may have prognostic implications for patient outcomes.

Gene→Variant (gene-first): ERBB2(2064):D769H ERBB2(2064):D769Y ERBB2(2064):I767M EGFR(1956):K753I ERBB2(2064):L755S ERBB2(2064):R678Q ERBB2(2064):S310F ERBB2(2064):S310Y ERBB2(2064):V842I

Genes: ERBB2(2064) EGFR(1956)

Variants: D769H D769Y I767M K753I L755S R678Q S310F S310Y V842I

[Paper-level Aggregated] PMCID: PMC7074098

Evidence Type(s): Prognostic, Oncogenic

Justification: Prognostic: The text indicates that BAP1 amplification is associated with significantly better survival (HR = 0.56, p = 0.005), suggesting a prognostic role for this variant in the context of overall survival in CM. Oncogenic: The presence of missense mutations in BAP1, including E30K, I643T, P629S, R417M, S143N, L416F, and R59W, suggests potential oncogenic significance, although their individual impacts on tumor behavior are described as having unknown significance.

Gene→Variant (gene-first): BAP1(8314):E30K BAP1(8314):I643T BAP1(8314):L416F BAP1(8314):P629S BAP1(8314):R417M BAP1(8314):R59W PMEL(6490):S143N

Genes: BAP1(8314) PMEL(6490)

Variants: E30K I643T L416F P629S R417M R59W S143N

[Paper-level Aggregated] PMCID: PMC7068240

Evidence Type(s): Prognostic, Oncogenic

Justification: Prognostic: The study indicates that high miR-31 expression is significantly associated with poorer mortality and shorter median survival time in patients with advanced CRC, suggesting its role as a prognostic biomarker. Oncogenic: The presence of the BRAF V600E mutation is associated with specific tumor characteristics and poorer outcomes, indicating its role in tumorigenesis in colorectal cancer.

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

Genes: BRAF(673)

Variants: V600E serine/threonine

[Paper-level Aggregated] PMCID: PMC7064492

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The presence of MAP2K1 (p.K57N) mutations in the endothelial cells suggests a role in the development of arteriovenous malformations, indicating that this variant may contribute to oncogenic processes in the context of vascular anomalies. Functional: The study investigates the effects of the MAP2K1 (p.K57N) mutation on local tissue overgrowth, demonstrating that the mutation influences the behavior of adjacent tissues, which supports a functional role of the variant in the pathology of arteriovenous malformations.

Gene→Variant (gene-first): MAP2K1(5604):p.K57N

Genes: MAP2K1(5604)

Variants: p.K57N

[Paper-level Aggregated] PMCID: PMC6938308

Evidence Type(s): Oncogenic, Diagnostic, Prognostic

Justification: Oncogenic: The text indicates that KRAS mutations (p.G12D and p.G12V) and BRAF mutations (p.V600E and p.Q636X) are linked to brain AVMs, suggesting these variants contribute to disease development. Diagnostic: The detection of somatic mutations in AVM specimens indicates that these mutations can be used to identify the presence of the disease in patients. Prognostic: The observation that two patients with BRAF mutations presented at an older age than other participants suggests that these mutations may be associated with age-related disease characteristics.

Gene→Variant (gene-first): KRAS(3845):G12D KRAS(3845):G12V BRAF(673):Q636X BRAF(673):V600E KRAS(3845):p.12G BRAF(673):p.600V KRAS(3845):p.G12D KRAS(3845):p.G12V BRAF(673):p.Q636X BRAF(673):p.V600E

Genes: KRAS(3845) BRAF(673)

Variants: G12D G12V Q636X V600E p.12G p.600V p.G12D p.G12V p.Q636X p.V600E

[Paper-level Aggregated] PMCID: PMC6843359

Evidence Type(s): Oncogenic, Predictive, Functional

Justification: Oncogenic: The S310F HER2 mutant is described as inducing receptor activation and forming active heterodimers with EGFR, suggesting its role in promoting cancer cell proliferation. Predictive: The text indicates that patients with the S310F mutation responded to trastuzumab with or without pertuzumab, suggesting that the presence of this mutation can predict treatment response. Functional: The S310F HER2 mutant's ability to interact with EGFR and its effects on HER2 phosphorylation and cell proliferation demonstrate its functional role in cellular signaling pathways.

Gene→Variant (gene-first): ERBB2(2064):G309 ERBB2(2064):G309A ERBB2(2064):G309E ERBB2(2064):S309A ERBB2(2064):S310 ERBB2(2064):S310F ERBB2(2064):S310Y

Genes: ERBB2(2064)

Variants: G309 G309A G309E S309A S310 S310F S310Y

[Paper-level Aggregated] PMCID: PMC6791388

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The text discusses the role of Serine 133 phosphorylation in CREB and its implications for cell survival and MEKi resistance, indicating a functional impact of the variant on cellular behavior. Oncogenic: The increased phosphorylation of CREB at Ser133 in leukemic cells is associated with promoting cell survival and resistance to MEK inhibitors, suggesting a potential role in oncogenesis.

Gene→Variant (gene-first): TP53(7157):S133 TP53(7157):Ser133 TP53(7157):Serine 133

Genes: TP53(7157)

Variants: S133 Ser133 Serine 133

[Paper-level Aggregated] PMCID: PMC6627713

Evidence Type(s): Oncogenic, Prognostic, Functional

Justification: Oncogenic: Several variants, including those in the TP53 and APC genes, are associated with cancer development, and specific mutations like p.Arg505Cys in FBXW7 have been reported to lead to loss of function, contributing to oncogenesis. Prognostic: The presence of certain variants, such as those in MAP2K1 and FBXW7, correlates with progression-free survival (PFS) outcomes, indicating their potential role in predicting disease progression. Functional: The variant p.Lys57Glu in MAP2K1 is associated with a gain of function of the MEK1 protein, indicating a functional impact on protein activity that may influence cancer pathways.

Gene→Variant (gene-first): FBXW7(55294):c.1268G>T FBXW7(55294):p.Gly423Val FBXW7(55294):c.1513C>T EGFR(1956):c.1798G>A FBXW7(55294):p.Arg505Cys BRAF(673):p.Asp600Asn MAP2K1(5604):c.169A>G MAP2K1(5604):c.199G>A MAP2K1(5604):p.Asp67Asn MAP2K1(5604):p.Lys57Glu KRAS(3845):c.183A>T KRAS(3845):p.Gln61His TP53(7157):c.275_276insGGCC APC(324):c.4098_4099delTCinsAT APC(324):c.4467_4468insCATTTTG APC(324):c.589_590insGAGTT APC(324):c.837_838InsG NF1(4763):c.5101A>T NF1(4763):c.638_639insA NF1(4763):p.Asn214Lys fs*2 NF1(4763):p.Lys1701Ter

Genes: FBXW7(55294) EGFR(1956) BRAF(673) MAP2K1(5604) KRAS(3845) TP53(7157) APC(324) NF1(4763)

Variants: c.1268G>T p.Gly423Val c.1513C>T c.1798G>A p.Arg505Cys p.Asp600Asn c.169A>G c.199G>A p.Asp67Asn p.Lys57Glu c.183A>T p.Gln61His c.275_276insGGCC c.4098_4099delTCinsAT c.4467_4468insCATTTTG c.589_590insGAGTT c.837_838InsG c.5101A>T c.638_639insA p.Asn214Lys fs*2 p.Lys1701Ter

[Paper-level Aggregated] PMCID: PMC6594036

Evidence Type(s): nan

Justification: No positive paragraphs to aggregate.

Gene→Variant (gene-first):

Genes:

Variants:

[Paper-level Aggregated] PMCID: PMC6549573

Evidence Type(s): Oncogenic, Predictive, Prognostic

Justification: Oncogenic: The KRAS G12D mutation is described as a characteristic of the lung adenocarcinomas being studied, indicating its role in the oncogenesis of these tumors. Predictive: The text mentions that KRAS G12D mutation alone is not a robust predictor of response to bortezomib, suggesting its potential role in predicting treatment outcomes, albeit not reliably. Prognostic: The overall survival and progression-free survival data provided in the study suggest that the presence of the KRAS G12D mutation may have implications for the prognosis of patients with advanced NSCLC.

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

Genes: KRAS(3845)

Variants: G12D

[Paper-level Aggregated] PMCID: PMC6547725

Evidence Type(s): Oncogenic, Functional, Predictive

Justification: Oncogenic: The text describes several RAS variants, including classical oncogenic mutations in KRAS and NRAS, and indicates that these mutations are associated with increased GTP loading and enhanced RAS signaling. Functional: The evidence discusses the impact of VMOS RAS variants on GTP hydrolysis and their interaction with GEFs and GAPs, suggesting alterations in their functional properties compared to wild type proteins. Predictive: The analysis of the VMOS RAS variants indicates potential changes in signaling capabilities, which could be used to predict the biological behavior of these variants in a clinical context.

Gene→Variant (gene-first): RASA1(5921):Gln61 KRAS(3845):p.G12A KRAS(3845):p.G13H KRAS(3845):p.Q22K KRAS(3845):p.G12V NRAS(4893):p.Q61L

Genes: RASA1(5921) KRAS(3845) NRAS(4893)

Variants: Gln61 p.G12A p.G13H p.Q22K p.G12V p.Q61L

[Paper-level Aggregated] PMCID: PMC6547681

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

Justification: Oncogenic: The G101V mutation in BCL-2 is associated with acquired resistance to venetoclax therapy in patients with chronic lymphocytic leukaemia, indicating its role in promoting cancer progression. Functional: The study describes how the G101V mutation alters the binding affinity of venetoclax to BCL-2, demonstrating a functional impact on drug interaction and resistance mechanisms. Predictive: The identification of the G101V mutation as a factor that reduces venetoclax affinity allows for predictions about patient responses to this therapy, suggesting that its presence may indicate a likelihood of treatment failure. Prognostic: The emergence of the G101V mutation in patients failing venetoclax therapy suggests it may serve as a prognostic marker for treatment outcomes in chronic lymphocytic leukaemia.

Gene→Variant (gene-first): BCL2(596):E152 BCL2(596):E152A BCL2(596):G101A BCL2(596):G101V BCL2(596):V101 BCL2(596):G101 BCL2(596):F104 BCL2(596):F104L BCL2(596):L104 BCL2(596):F104C

Genes: BCL2(596)

Variants: E152 E152A G101A G101V V101 G101 F104 F104L L104 F104C