Submissions for variant NM_000251.3(MSH2):c.1405C>G (p.Leu469Val)

dbSNP: rs780702096

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000550095	SCV000625262	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-11-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000575666	SCV000669740	likely benign	Hereditary cancer-predisposing syndrome	2022-01-20	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
GeneKor MSA	RCV000575666	SCV000822043	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000575666	SCV001360144	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-24	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 469 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in a cohort of individuals with a personal or family history of breast and/or ovarian cancer (PMID: 31159747). This variant has been identified in 1/251256 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
GeneDx	RCV001755785	SCV001985258	uncertain significance	not provided	2019-11-19	criteria provided, single submitter	clinical testing	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 31159747)
PreventionGenetics, part of Exact Sciences	RCV004527635	SCV004112698	uncertain significance	MSH2-related disorder	2023-07-05	criteria provided, single submitter	clinical testing	The MSH2 c.1405C>G variant is predicted to result in the amino acid substitution p.Leu469Val. This variant was reported in an individuals with breast cancer or undergoing testing for cancer predisposition (Table S5, Tsaousis. 2019. PubMed ID: 31159747; Castillo-Guardiola. 2022. PubMed ID: 35245693). This variant is reported in 0.00088% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/2-47690188-C-G), and is interpreted as uncertain and likely benign in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/455490/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
All of Us Research Program, National Institutes of Health	RCV004003733	SCV004833285	uncertain significance	Lynch syndrome	2024-02-05	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 469 of the MSH2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). This variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (internally defined LOF score threshold <= -1.32, PMID: 33357406). This variant has been reported in a cohort of individuals with a personal or family history of breast and/or ovarian cancer (PMID: 31159747). This variant has been identified in 1/251256 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.