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    1. karim2001khoury 19 Feb 2026
      The HER2 S310F Mutant Can Form an Active Heterodimer with the EGFR, Which Can Be Inhibited by Cetuximab but Not by Trastuzumab as well as Pertuzumab

      [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

      CIViC paper-level aggregated PMC6843359
    2. karim2001khoury 19 Feb 2026
      G309 or S310 mutations on the HER2 extracellular domain II induce receptor activation. Clinically, S310F is most frequent among HER2 extracellular domain mutations and patients with the S310F mutation without HER2 amplif

      [Paragraph-level] PMCID: PMC6843359 Section: ABSTRACT PassageIndex: 1

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the response of patients with the S310F mutation to trastuzumab and pertuzumab treatments, indicating a correlation between the variant and treatment response. Functional: The passage describes how the S310F mutation alters the ability of the HER2 receptor to form homodimers or heterodimers and its interaction with EGFR, demonstrating a change in molecular function.

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

      Genes: 2064

      Variants: G309A G309E S310 S310F S310Y

      CIViC paragraph-level PMC6843359 Predictive Functional
    3. karim2001khoury 19 Feb 2026
      After transfection, the cells were allowed to grow for 24 h and then lysed. The level of EGFR-mCherry and wild-type and S310F HER2-eGFP in the cell lysate was determined by measuring the fluorescence intensity. After a c

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the S310F variant of HER2 interacts with EGFR and compares its efficiency to wild-type HER2, indicating an alteration in molecular function.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Functional
    4. karim2001khoury 19 Feb 2026
      Single molecule interaction analysis was performed to determine whether the S310F HER mutant formed a heterodimer with the EGFR. We constructed a bicistronic mammalian expression vector encoding EGFR-mCherry and S310F HE

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the interaction of the S310F HER2 mutant with EGFR and its altered reactivity to specific antibodies, indicating a change in molecular function. Oncogenic: The S310F HER2 variant is implicated in altered interactions that may contribute to tumor development or progression, as suggested by the context of the study involving cancer-related proteins.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Functional Oncogenic
    5. karim2001khoury 19 Feb 2026
      3.4. Single-Molecular Interaction Analysis Demonstrated That the S310F HER2 Mutant Formed Heterodimers with the EGFR

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Functional

      Justification: Functional: The passage indicates that the S310F variant alters the molecular interaction by forming heterodimers with EGFR, suggesting a change in biochemical function.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Functional
    6. karim2001khoury 19 Feb 2026
      We tested the effects of anti-HER2 agents on 5637 cell proliferation and the level of HER2 phosphorylation at Y1221 and Y1222 residues. The cells were incubated with pertuzumab, trastuzumab and lapatinib for 96 h, lysed

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the effects of anti-HER2 agents on cell proliferation and HER2 phosphorylation in relation to the S310F HER2 mutant, indicating a correlation with response to specific therapies. Oncogenic: The S310F variant is implicated in the phosphorylation process and cell proliferation in cancer cells, suggesting its role in tumor development or progression.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Predictive Oncogenic
    7. karim2001khoury 19 Feb 2026
      3.3. EGFR Activates S310F HER2 Mutant in 5637 Cell

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage indicates that the S310F variant in HER2 is associated with activation in a cell line, suggesting its role in tumor development or progression.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Oncogenic
    8. karim2001khoury 19 Feb 2026
      To confirm the expression of the S310F HER2 mutant in 5637 cells, we used immunoprecipitation experiments. We hypothesized that if the cells expressed the S310F HER2 mutant, it would not be immunoprecipitated by pertuzum

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the expression of the S310F HER2 mutant and its interaction with pertuzumab, indicating that the variant alters the molecular function of HER2 in terms of immunoprecipitation. Oncogenic: The S310F variant is described in the context of its expression in cancer cell lines, suggesting that it may contribute to tumor development or progression.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Functional Oncogenic
    9. karim2001khoury 19 Feb 2026
      We searched literatures to identify a human cell line expressing the S310F mutant and found that bladder cancer cell line 5637 expressed the mutant. To test the allelic expression of the S310F HER2 mutant in the 5637 cel

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the expression and detection of the S310F HER2 mutant in a bladder cancer cell line, indicating that the variant alters the molecular function of the HER2 protein as it is being analyzed for its presence on the cell surface. Oncogenic: The S310F variant is discussed in the context of a bladder cancer cell line, suggesting that it may contribute to tumor development or progression, which aligns with the definition of an oncogenic variant.

      Gene→Variant (gene-first): 2064:S310 2064:S310F

      Genes: 2064

      Variants: S310 S310F

      CIViC paragraph-level PMC6843359 Functional Oncogenic
    11. karim2001khoury 19 Feb 2026
      A construct encoding the S310F HER2 extracellular domain fused to a human Fc domain of immunoglobulin heavy chain was prepared and cloned into a mammalian expression vector. For comparison, the expression vectors encodin

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the binding interactions of various HER2 mutants with the antibodies pertuzumab and trastuzumab, indicating their response to these therapies. Functional: The passage describes the preparation and purification of recombinant fusion proteins and their binding characteristics, which suggests alterations in molecular function related to the HER2 mutants.

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

      Genes: 2064

      Variants: G309 G309A G309E S309A S310 S310F S310Y

      CIViC paragraph-level PMC6843359 Predictive Functional
    12. karim2001khoury 19 Feb 2026
      3.1. The Recombinant S310F Mutant Is Not Reactive to Pertuzumab but Binds to Trastuzumab

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 2

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage indicates that the S310F mutant is not reactive to Pertuzumab, suggesting a correlation with resistance to this specific therapy. Functional: The passage discusses the binding characteristics of the S310F mutant, indicating an alteration in molecular function related to its interaction with Trastuzumab.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Predictive Functional
    13. karim2001khoury 19 Feb 2026
      After transfection, the cells were allowed to grow for 24 h and then lysed. The level of EGFR-mCherry and wild-type and S310F HER2-eGFP in the cell lysate was determined by measuring the fluorescence intensity. After a c

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 11

      Evidence Type(s): Functional

      Justification: Functional: The passage discusses how the S310F variant of HER2 interacts with EGFR and compares its efficiency to wild-type HER2, indicating an alteration in molecular function.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Functional
    14. karim2001khoury 19 Feb 2026
      Single molecule interaction analysis was performed to determine whether the S310F HER mutant formed a heterodimer with the EGFR. We constructed a bicistronic mammalian expression vector encoding EGFR-mCherry and S310F HE

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 10

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the interaction of the S310F HER2 mutant with EGFR and its altered reactivity to specific antibodies, indicating a change in molecular function. Oncogenic: The S310F HER2 variant is implicated in altered interactions that may contribute to tumor development or progression, as suggested by the context of the study involving cancer-related proteins.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Functional Oncogenic
    15. karim2001khoury 19 Feb 2026
      3.4. Single-Molecular Interaction Analysis Demonstrated That the S310F HER2 Mutant Formed Heterodimers with the EGFR

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 9

      Evidence Type(s): Functional

      Justification: Functional: The passage indicates that the S310F variant alters the molecular interaction by forming heterodimers with EGFR, suggesting a change in biochemical function.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Functional
    16. karim2001khoury 19 Feb 2026
      We tested the effects of anti-HER2 agents on 5637 cell proliferation and the level of HER2 phosphorylation at Y1221 and Y1222 residues. The cells were incubated with pertuzumab, trastuzumab and lapatinib for 96 h, lysed

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 8

      Evidence Type(s): Predictive, Oncogenic

      Justification: Predictive: The passage discusses the effects of anti-HER2 agents on cell proliferation and HER2 phosphorylation in relation to the S310F HER2 mutant, indicating a correlation with response to specific therapies. Oncogenic: The S310F variant is implicated in the phosphorylation process and cell proliferation in cancer cells, suggesting its role in tumor development or progression.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Predictive Oncogenic
    17. karim2001khoury 19 Feb 2026
      3.3. EGFR Activates S310F HER2 Mutant in 5637 Cell

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 7

      Evidence Type(s): Oncogenic

      Justification: Oncogenic: The passage indicates that the S310F variant in HER2 is associated with activation in a cell line, suggesting its role in tumor development or progression.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Oncogenic
    18. karim2001khoury 19 Feb 2026
      To confirm the expression of the S310F HER2 mutant in 5637 cells, we used immunoprecipitation experiments. We hypothesized that if the cells expressed the S310F HER2 mutant, it would not be immunoprecipitated by pertuzum

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 6

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the expression of the S310F HER2 mutant and its interaction with pertuzumab, indicating that the variant alters the molecular function of HER2 in terms of immunoprecipitation. Oncogenic: The S310F variant is described in the context of its expression in cancer cell lines, suggesting that it may contribute to tumor development or progression.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Functional Oncogenic
    19. karim2001khoury 19 Feb 2026
      We searched literatures to identify a human cell line expressing the S310F mutant and found that bladder cancer cell line 5637 expressed the mutant. To test the allelic expression of the S310F HER2 mutant in the 5637 cel

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 5

      Evidence Type(s): Functional, Oncogenic

      Justification: Functional: The passage discusses the expression and detection of the S310F HER2 mutant in a bladder cancer cell line, indicating that the variant alters the molecular function of the HER2 protein as it is being analyzed for its presence on the cell surface. Oncogenic: The S310F variant is discussed in the context of a bladder cancer cell line, suggesting that it may contribute to tumor development or progression, which aligns with the definition of an oncogenic variant.

      Gene→Variant (gene-first): 2064:S310 2064:S310F

      Genes: 2064

      Variants: S310 S310F

      CIViC paragraph-level PMC6843359 Functional Oncogenic
    21. karim2001khoury 19 Feb 2026
      A construct encoding the S310F HER2 extracellular domain fused to a human Fc domain of immunoglobulin heavy chain was prepared and cloned into a mammalian expression vector. For comparison, the expression vectors encodin

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 3

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage discusses the binding interactions of various HER2 mutants with the antibodies pertuzumab and trastuzumab, indicating their response to these therapies. Functional: The passage describes the preparation and purification of recombinant fusion proteins and their binding characteristics, which suggests alterations in molecular function related to the HER2 mutants.

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

      Genes: 2064

      Variants: G309 G309A G309E S309A S310 S310F S310Y

      CIViC paragraph-level PMC6843359 Predictive Functional
    22. karim2001khoury 19 Feb 2026
      3.1. The Recombinant S310F Mutant Is Not Reactive to Pertuzumab but Binds to Trastuzumab

      [Paragraph-level] PMCID: PMC6843359 Section: RESULTS PassageIndex: 2

      Evidence Type(s): Predictive, Functional

      Justification: Predictive: The passage indicates that the S310F mutant is not reactive to Pertuzumab, suggesting a correlation with resistance to this specific therapy. Functional: The passage discusses the binding characteristics of the S310F mutant, indicating an alteration in molecular function related to its interaction with Trastuzumab.

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

      Genes: 2064

      Variants: S310F

      CIViC paragraph-level PMC6843359 Predictive Functional
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    pmc.ncbi.nlm.nih.gov/articles/PMC6843359/pdf/biomolecules-09-00629.pdf