[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: 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: 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