Submissions for variant NM_000251.3(MSH2):c.507A>G (p.Ile169Met)

dbSNP: rs748762580

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000203760	SCV000260481	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-12-18	criteria provided, single submitter	clinical testing
Counsyl	RCV000662969	SCV000785948	uncertain significance	Lynch syndrome 1	2018-01-18	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000771214	SCV000903266	uncertain significance	Hereditary cancer-predisposing syndrome	2024-01-03	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 169 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251484 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.
Mendelics	RCV000662969	SCV001135704	uncertain significance	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000771214	SCV001185395	likely benign	Hereditary cancer-predisposing syndrome	2023-11-21	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	RCV001569238	SCV001793277	uncertain significance	not provided	2019-08-29	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
Myriad Genetics, Inc.	RCV000662969	SCV004018277	likely benign	Lynch syndrome 1	2023-03-17	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
CeGaT Center for Human Genetics Tuebingen	RCV001569238	SCV004146068	likely benign	not provided	2023-12-01	criteria provided, single submitter	clinical testing	MSH2: BP1, BP4
All of Us Research Program, National Institutes of Health	RCV003997617	SCV004830366	uncertain significance	Lynch syndrome	2024-03-05	criteria provided, single submitter	clinical testing	This missense variant replaces isoleucine with methionine at codon 169 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). To our knowledge, this variant has not been reported in individuals affected with MSH2-related disorders in the literature. This variant has been identified in 1/251484 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001569238	SCV005623671	uncertain significance	not provided	2024-05-10	criteria provided, single submitter	clinical testing	The MSH2 c.507A>G (p.Ile169Met) variant has been reported in the published literature in an individual with breast cancer (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2). A published functional study reports that this variant is not damaging to protein function (PMID: 33357406 (2021)). The frequency of this variant in the general population, 0.000004 (1/251484 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 benign. Based on the available information, we are unable to determine the clinical significance of this variant.