Submissions for variant NM_000251.3(MSH2):c.631G>A (p.Gly211Arg)

gnomAD frequency: 0.00001  dbSNP: rs587780689

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000122991	SCV000166284	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-25	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000222170	SCV000274682	likely benign	Hereditary cancer-predisposing syndrome	2023-07-20	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.
GeneDx	RCV000486574	SCV000566428	uncertain significance	not provided	2016-04-29	criteria provided, single submitter	clinical testing	This variant is denoted MSH2 c.631G>A at the cDNA level, p.Gly211Arg (G211R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH2 Gly211Arg was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH2 Gly211Arg occurs at a position that is not conserved and is located within the Connector domain (Lutzen 2008). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH2 Gly211Arg is pathogenic or benign. We consider it to be a variant of uncertain significance.
Color Diagnostics, LLC DBA Color Health	RCV000222170	SCV001350533	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-18	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 211 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has been identified in 2/250614 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV004526617	SCV005039789	uncertain significance	not specified	2024-03-19	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000486574	SCV005623679	uncertain significance	not provided	2023-11-20	criteria provided, single submitter	clinical testing	The MSH2 c.631G>A (p.Gly211Arg) variant has been reported in the published literature in individuals with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). The frequency of this variant in the general population, 0.000008 (2/250614 chromosomes (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant.