[Paper-level Aggregated] PMCID: PMC8881279

Evidence Type(s): Functional

Summary: Mutation: E401G | Summary: The ERBB2 E401G variant alters molecular function by enhancing C-terminal phosphorylation, stabilizing the dimer interface of the HER2-EGFR complex, and activating the MAPK pathway, contributing to changes in proliferative and invasive capacities of cancer cells. It is associated with increased phosphorylation of HER2 and ERK, and does not contribute to the formation of disulfide-linked dimers.

Evidence Type: Functional Mutation: S310F | Summary: The ERBB2 S310F variant alters molecular function by enhancing C-terminal phosphorylation, stabilizing the dimer interface of the HER2-EGFR complex, and activating the MAPK pathway, leading to a significantly higher proliferation rate in cancer cells. It does not show increases in HER2 dimers.

Evidence Type: Functional Mutation: E321G | Summary: The ERBB2 E321G variant alters molecular function by forming disulfide-linked dimers and is involved in activation mechanisms related to dimer formation and C-terminal phosphorylation.

Evidence Type: Functional Mutation: D845A | Summary: The ERBB2 D845A variant is described as a kinase domain inactivating variant and is part of the evaluation of functional properties related to activation mechanisms.

Gene→Variant (gene-first): FANCC(2176):E401G ERBB2(2064):S310F TP53(7157):E321G ERBB2(2064):D845A

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

Variants: E401G S310F E321G D845A

[Paper-level Aggregated] PMCID: PMC8881279

Evidence Type(s): Oncogenic

Summary: Mutation: E401G | Summary: The ERBB2 E401G variant is identified as a somatic mutation that contributes to tumor development, associated with high allele fraction and ERBB2 gene amplification. It is linked to increased phosphorylation levels of HER2 and EGFR, and is described as an activating mutation, indicating its role in tumor growth and progression.

Evidence Type: Oncogenic Mutation: S310F | Summary: The HER2 S310F mutation is associated with increased phosphorylation levels of HER2 and EGFR, and is classified as an activating mutation, suggesting its contribution to tumor development or progression.

Evidence Type: Oncogenic Mutation: E321G | Summary: The E321G variant is classified as an activating mutation, suggesting its contribution to tumor development or progression.

Gene→Variant (gene-first): FANCC(2176):E401G ERBB2(2064):S310F TP53(7157):E321G

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

Variants: E401G S310F E321G

[Paper-level Aggregated] PMCID: PMC8881279

Evidence Type(s): Diagnostic

Summary: 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): FANCC(2176):E401G

Genes: FANCC(2176)

Variants: E401G

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

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: E401G | Summary: The ERBB2 E401G variant alters molecular function by enhancing C-terminal phosphorylation and maintaining the stability of the EGFR-HER2 heterodimer. Evidence Type: Functional | Mutation: S310F | Summary: The ERBB2 S310F variant also alters molecular function by enhancing C-terminal phosphorylation and maintaining the stability of the EGFR-HER2 heterodimer.

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

Genes: 2176 2064

Variants: E401G S310F

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

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: E401G | Summary: The E401G variant was analyzed for its biological effects and mechanisms through molecular dynamics simulation, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: E401G | Summary: The E401G variant is described as an activating mutation, suggesting its contribution to tumor development or progression. Evidence Type: Functional | Mutation: S310F | Summary: The S310F variant was included in the analysis of ERBB2 expression vectors, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: S310F | Summary: The S310F variant is known to be an activating mutation, suggesting its role in tumor development or progression. Evidence Type: Functional | Mutation: E321G | Summary: The E321G variant was part of the ERBB2 expression vectors analysis, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: E321G | Summary: The E321G variant is classified as an activating mutation, suggesting its contribution to tumor development or progression.

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

Genes: 7157 2176 2064

Variants: E321G E401G S310F

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

Evidence Type(s): Functional

Summary: Evidence Type: Functional | Mutation: 1157A > G | Summary: The variant 1157A > G (E401G) is associated with efforts to clarify its biological functions and mechanisms of activation, indicating a focus on its molecular function.

Gene→Variant (gene-first): 4609:1157A > G 2176:E401G

Genes: 4609 2176

Variants: 1157A > G E401G

[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

[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)

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E401G and S310F alter molecular function by enhancing C-terminal phosphorylation and maintaining the stability of the EGFR-HER2 heterodimer. Oncogenic: The passage indicates that ERBB2 E401G-transduced cells exhibit increased tumor growth capacity in vivo, suggesting that this variant contributes to tumor development or progression.

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

Genes: 2176 2064

Variants: E401G S310F

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the evaluation of the phosphorylation of human epidermal growth factor receptor 2 and related proteins, as well as the investigation of the biological effects of the ERBB2 E401G variant, indicating an alteration in molecular function. Oncogenic: The mention of S310F and E321G as known activating mutations suggests that these variants contribute to tumor development or progression, aligning with the oncogenic evidence type.

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

Genes: 7157 2176 2064

Variants: E321G E401G S310F

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses the aim to clarify the biological functions of the ERBB2 E401G variant, indicating an interest in how this variant alters molecular or biochemical function.

Gene→Variant (gene-first): 4609:1157A > G 2176:E401G

Genes: 4609 2176

Variants: 1157A > G E401G

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

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the tumor forming capacity of cells expressing the ERBB2 E401G variant, indicating that this somatic variant contributes to tumor development as evidenced by increased tumor growth in vivo.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the effects of the ERBB2 E401G and S310F variants on the proliferative and invasive capacities of cancer cells, indicating that these variants alter molecular or biochemical functions related to cell behavior. Oncogenic: The evaluation of the proliferative and invasive capacities of cells expressing the ERBB2 variants suggests that these somatic variants contribute 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: 15

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E401G and S310F alter the phosphorylation of downstream signaling pathway proteins, indicating a change in molecular function related to the MAPK pathway. Oncogenic: The evidence suggests that the variants contribute to tumor development or progression by activating signaling pathways associated with cancer, specifically through the ERBB2 dimerization and its effects on downstream signaling.

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

Justification: Functional: The passage discusses how the E401G and S310F mutations affect the dimer interface stability of the EGFR-HER2 complex, indicating that these variants alter molecular interactions and stability.

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): None

Justification: Not enough information in this passage.

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

Justification: Functional: The passage indicates that the variant p.(E401G) alters the stability of the ligand-free EGFR HER2 heterodimer, which suggests a change in molecular function.

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

Genes: 2176

Variants: p.(E401G)

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E401G and S310F lead to increased phosphorylation levels of HER2 and EGFR, indicating that these variants alter molecular function related to protein activity. Oncogenic: The context of the passage suggests that the variants E401G and S310F contribute to tumor development or progression by enhancing the phosphorylation of key HER family proteins involved in oncogenesis.

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

Justification: Functional: The passage discusses the identification of potential dimerization partners of the HER2 E401G protein, indicating that the variant alters molecular interactions.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants S310F and E401G alter the C-terminal phosphorylation of HER2, indicating 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: 6

Evidence Type(s): Functional

Justification: Functional: The passage discusses the ability of the variants E321G, E401G, and S310F to form disulfide-linked dimers, indicating that these variants alter molecular function related to protein interactions.

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

Justification: Functional: The passage mentions the evaluation of mechanisms for multiple ERBB2 variants, including E321G, E401G, S310F, and D845A, which suggests that these variants are being assessed for their biochemical functions.

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

Justification: Functional: The passage indicates that ERBB2 E401G has functional properties similar to S310F, suggesting that these variants alter 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

Justification: Oncogenic: The passage describes the ERBB2 E401G variant as a somatic mutation that is associated with ERBB2 gene amplification, indicating its contribution to tumor development or progression. Functional: The passage mentions that multiple computational tools supported a deleterious effect of the ERBB2 E401G variant on the encoded gene product, suggesting that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

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

Evidence Type(s): Diagnostic

Justification: Diagnostic: The passage mentions the detection of the ERBB2 E401G variant of uncertain significance (VUS) in a patient, indicating its use in defining or classifying a disease context, specifically in a patient with cancer of unknown primary (CUP).

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E401G and S310F alter molecular function by enhancing C-terminal phosphorylation and maintaining the stability of the EGFR-HER2 heterodimer. Oncogenic: The passage indicates that ERBB2 E401G-transduced cells exhibit increased tumor growth capacity in vivo, suggesting that this variant contributes to tumor development or progression.

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

Genes: 2176 2064

Variants: E401G S310F

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the evaluation of the phosphorylation of human epidermal growth factor receptor 2 and related proteins, as well as the investigation of the biological effects of the ERBB2 E401G variant, indicating an alteration in molecular function. Oncogenic: The mention of S310F and E321G as known activating mutations suggests that these variants contribute to tumor development or progression, aligning with the oncogenic evidence type.

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

Genes: 7157 2176 2064

Variants: E321G E401G S310F

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses the aim to clarify the biological functions of the ERBB2 E401G variant, indicating an interest in how this variant alters molecular or biochemical function.

Gene→Variant (gene-first): 4609:1157A > G 2176:E401G

Genes: 4609 2176

Variants: 1157A > G E401G

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

Evidence Type(s): Oncogenic

Justification: Oncogenic: The passage discusses the tumor forming capacity of cells expressing the ERBB2 E401G variant, indicating that this somatic variant contributes to tumor development as evidenced by increased tumor growth in vivo.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses the effects of the ERBB2 E401G and S310F variants on the proliferative and invasive capacities of cancer cells, indicating that these variants alter molecular or biochemical functions related to cell behavior. Oncogenic: The evaluation of the proliferative and invasive capacities of cells expressing the ERBB2 variants suggests that these somatic variants contribute 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: 15

Evidence Type(s): None

Justification: Not enough information in this passage.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E401G and S310F alter the phosphorylation of downstream signaling pathway proteins, indicating a change in molecular function related to the MAPK pathway. Oncogenic: The evidence suggests that the variants contribute to tumor development or progression by activating signaling pathways associated with cancer, specifically through the ERBB2 dimerization and its effects on downstream signaling.

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

Justification: Functional: The passage discusses how the E401G and S310F mutations affect the dimer interface stability of the EGFR-HER2 complex, indicating that these variants alter molecular interactions and stability.

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): None

Justification: Not enough information in this passage.

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

Justification: Functional: The passage indicates that the variant p.(E401G) alters the stability of the ligand-free EGFR HER2 heterodimer, which suggests a change in molecular function.

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

Genes: 2176

Variants: p.(E401G)

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

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variants E401G and S310F lead to increased phosphorylation levels of HER2 and EGFR, indicating that these variants alter molecular function related to protein activity. Oncogenic: The context of the passage suggests that the variants E401G and S310F contribute to tumor development or progression by enhancing the phosphorylation of key HER family proteins involved in oncogenesis.

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

Justification: Functional: The passage discusses the identification of potential dimerization partners of the HER2 E401G protein, indicating that the variant alters molecular interactions.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

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

Evidence Type(s): Functional

Justification: Functional: The passage discusses how the variants S310F and E401G alter the C-terminal phosphorylation of HER2, indicating 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: 6

Evidence Type(s): Functional

Justification: Functional: The passage discusses the ability of the variants E321G, E401G, and S310F to form disulfide-linked dimers, indicating that these variants alter molecular function related to protein interactions.

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

Justification: Functional: The passage mentions the evaluation of mechanisms for multiple ERBB2 variants, including E321G, E401G, S310F, and D845A, which suggests that these variants are being assessed for their biochemical functions.

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

Justification: Functional: The passage indicates that ERBB2 E401G has functional properties similar to S310F, suggesting that these variants alter 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

Justification: Oncogenic: The passage describes the ERBB2 E401G variant as a somatic mutation that is associated with ERBB2 gene amplification, indicating its contribution to tumor development or progression. Functional: The passage mentions that multiple computational tools supported a deleterious effect of the ERBB2 E401G variant on the encoded gene product, suggesting that it alters molecular or biochemical function.

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G

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

Evidence Type(s): Diagnostic

Justification: Diagnostic: The passage mentions the detection of the ERBB2 E401G variant of uncertain significance (VUS) in a patient, indicating its use in defining or classifying a disease context, specifically in a patient with cancer of unknown primary (CUP).

Gene→Variant (gene-first): 2176:E401G

Genes: 2176

Variants: E401G