ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.422T>C (p.Met141Thr)

gnomAD frequency: 0.00001  dbSNP: rs768313658
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759834 SCV000566957 uncertain significance not provided 2018-10-26 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.422T>C at the cDNA level, p.Met141Thr (M141T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. MSH2 Met141Thr was observed at an allele frequency of 0.01% (2/17248) in individuals of East Asian ancestry in large population cohorts (Lek 2016). This variant is located in the connector domain (L?tzen 2008, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH2 Met141Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759834 SCV000889439 uncertain significance not provided 2017-11-17 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000773079 SCV000906513 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-05 criteria provided, single submitter clinical testing This missense variant replaces methionine with threonine at codon 141 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 2/251414 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.
Invitae RCV001246708 SCV001420084 likely benign Hereditary nonpolyposis colorectal neoplasms 2023-07-29 criteria provided, single submitter clinical testing
Ambry Genetics RCV000773079 SCV002632799 likely benign Hereditary cancer-predisposing syndrome 2023-05-22 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.
Baylor Genetics RCV003470539 SCV004196827 uncertain significance Lynch syndrome 1 2023-05-25 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV004002296 SCV004830221 uncertain significance Lynch syndrome 2023-05-04 criteria provided, single submitter clinical testing This missense variant replaces methionine with threonine at codon 141 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 2/251414 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.

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