Submissions for variant NM_000251.3(MSH2):c.763A>G (p.Ser255Gly)

gnomAD frequency: 0.00001  dbSNP: rs761529282

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000222095	SCV000275893	likely benign	Hereditary cancer-predisposing syndrome	2022-12-02	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.
Invitae	RCV000526634	SCV000625460	likely benign	Hereditary nonpolyposis colorectal neoplasms	2023-10-13	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000222095	SCV000685128	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 255 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). TThis 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 not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251290 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000757937	SCV000886466	likely benign	Lynch syndrome	2018-05-09	criteria provided, single submitter	research	The MSH2 variant designated as NM_000251.2: c.763A>G (p.S255G) is classified as likely benign. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 0.08 to 1 that this allele explains cancer in the family (Thompson, et al., 2003, PMID:2900794). Computer software prediction programs also suggest the MSH2 p.S255G change is benign. Additionally, in the observed family, the variant co-occurs with a likely pathogenic variant in the MSH6 gene (p.R1076C). Immunohistochemical studies of endometrial tumor from one family member with the variant showed loss of the MSH6 protein, but no loss of IHC staining for MSH2, which is consistent with the likely pathogenic variant in the MSH6 gene. Together, this information is not consistent with a pathogenic mutation in MSH2. Bayesian analysis integrating data (Tavtigian et al, 2018, PMID:29300386) gives less than 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter MSH2 function or modify risk for Lynch syndrome. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
All of Us Research Program, National Institutes of Health	RCV000757937	SCV004829127	uncertain significance	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with glycine at codon 255 of the MSH2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). TThis 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 not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251290 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.