[Paper-level Aggregated] PMCID: PMC7820803

Evidence Type(s): Functional

Summary: Mutation: p.Ala636Pro | Summary: The p.Ala636Pro variant is associated with a destabilizing effect on MSH2 protein expression and alters the molecular function of the MMR machinery. It restores 6-TG sensitivity in a functional assay and is linked to a significant depletion of deleterious scores, indicating alterations in molecular or biochemical function.

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

Genes: MSH2(4436)

Variants: p.Ala636Pro

[Paper-level Aggregated] PMCID: PMC7820803

Evidence Type(s): Oncogenic

Summary: Mutation: p.Ala636Pro | Summary: The p.Ala636Pro variant is described as a pathogenic founder allele and is associated with MMR deficiency, contributing to tumor development or progression. Its enrichment in mixed cultures and selected cell pools under selective conditions suggests a significant role in tumorigenesis, particularly in the context of bi-allelic MMR loss related to pediatric-onset cancer syndromes such as Lynch syndrome.

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

Genes: MSH2(4436)

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.Ala636Pro | Summary: The variant p.Ala636Pro is associated with a significant depletion of deleterious scores in a functional assay, indicating that it alters molecular or biochemical function. Evidence Type: Oncogenic | Mutation: p.Ala636Pro | Summary: The variant p.Ala636Pro is implicated in the context of bi-allelic MMR loss, which is known to contribute to tumor development in pediatric-onset cancer syndromes such as Lynch syndrome.

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

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic

Summary: Evidence Type: Oncogenic | Mutation: p.Ala636Pro | Summary: The mutation p.Ala636Pro in MSH2 is associated with MMR deficiency and contributes to tumor development, as indicated by its enrichment in selected cell pools under selective conditions.

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

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.Ala636Pro | Summary: The p.Ala636Pro mutant variant of MSH2 was shown to restore 6-TG sensitivity in a functional assay, indicating that it alters the molecular function of the MMR machinery. Evidence Type: Oncogenic | Mutation: p.Ala636Pro | Summary: The enrichment of barcodes linked to the pathogenic variant p.Ala636Pro in mixed cultures suggests that this somatic variant contributes to tumor development or progression by affecting MMR function.

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

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Summary: Evidence Type: Functional | Mutation: p.Ala636Pro | Summary: The p.Ala636Pro variant is associated with a destabilizing effect on MSH2 protein expression, indicating an alteration in molecular function. Evidence Type: Oncogenic | Mutation: p.Ala636Pro | Summary: The p.Ala636Pro variant is described as a pathogenic founder allele, suggesting its contribution to tumor development or progression.

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

Genes: 4436

Variants: p.Ala636Pro

[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

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant p.Ala636Pro scored as deleterious in an assay, indicating that it alters molecular or biochemical function. Oncogenic: The context of the passage suggests that the variant is associated with bi-allelic MMR loss, which contributes to tumor development in pediatric-onset cancer syndromes, indicating its role in oncogenesis.

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

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the selection of MSH2 mutant cells, specifically the p.Ala636Pro variant, in the context of MMR deficiency, indicating that this somatic variant contributes to tumor development or progression. Functional: The passage describes the behavior of the p.Ala636Pro variant in a selective environment, suggesting that it alters the molecular function of the MSH2 protein, as evidenced by the enrichment of these cells under selective conditions.

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

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.Ala636Pro variant affects the sensitivity to 6-thioguanine, indicating that it alters the molecular function of MSH2 in the context of mismatch repair. Oncogenic: The passage implies that the p.Ala636Pro variant is pathogenic and contributes to the resistance of cells to 6-thioguanine, suggesting a role in tumor development or progression.

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

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.Ala636Pro variant affects the expression levels of MSH2 protein, indicating that it alters molecular function by being barely detectable compared to wild-type MSH2, which demonstrates its destabilizing effect. Oncogenic: The passage describes the use of the p.Ala636Pro variant in a model to disrupt mismatch repair (MMR), suggesting that this somatic variant contributes to tumor development or progression by affecting MSH2 function.

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

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 13

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the variant p.Ala636Pro scored as deleterious in an assay, indicating that it alters molecular or biochemical function. Oncogenic: The context of the passage suggests that the variant is associated with bi-allelic MMR loss, which contributes to tumor development in pediatric-onset cancer syndromes, indicating its role in oncogenesis.

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

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 7

Evidence Type(s): Oncogenic, Functional

Justification: Oncogenic: The passage discusses the selection of MSH2 mutant cells, specifically the p.Ala636Pro variant, in the context of MMR deficiency, indicating that this somatic variant contributes to tumor development or progression. Functional: The passage describes the behavior of the p.Ala636Pro variant in a selective environment, suggesting that it alters the molecular function of the MSH2 protein, as evidenced by the enrichment of these cells under selective conditions.

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

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 4

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.Ala636Pro variant affects the sensitivity to 6-thioguanine, indicating that it alters the molecular function of MSH2 in the context of mismatch repair. Oncogenic: The passage implies that the p.Ala636Pro variant is pathogenic and contributes to the resistance of cells to 6-thioguanine, suggesting a role in tumor development or progression.

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

Genes: 4436

Variants: p.Ala636Pro

[Paragraph-level] PMCID: PMC7820803 Section: RESULTS PassageIndex: 3

Evidence Type(s): Functional, Oncogenic

Justification: Functional: The passage discusses how the p.Ala636Pro variant affects the expression levels of MSH2 protein, indicating that it alters molecular function by being barely detectable compared to wild-type MSH2, which demonstrates its destabilizing effect. Oncogenic: The passage describes the use of the p.Ala636Pro variant in a model to disrupt mismatch repair (MMR), suggesting that this somatic variant contributes to tumor development or progression by affecting MSH2 function.

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

Genes: 4436

Variants: p.Ala636Pro