ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.968C>G (p.Ser323Cys)

gnomAD frequency: 0.00003  dbSNP: rs63750732
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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222150 SCV000273520 likely benign Hereditary cancer-predisposing syndrome 2023-04-10 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.
Counsyl RCV000412467 SCV000488063 uncertain significance Lynch syndrome 1 2015-12-18 criteria provided, single submitter clinical testing
Labcorp Genetics (formerly Invitae), Labcorp RCV000524426 SCV000548205 benign Hereditary nonpolyposis colorectal neoplasms 2024-11-13 criteria provided, single submitter clinical testing
GeneDx RCV000480555 SCV000565187 uncertain significance not provided 2021-03-29 criteria provided, single submitter clinical testing Identified in at least two individuals with colorectal cancer, one of whom had corresponding tumors with microsatellite instability (Akiyama 1997, Bai 1999); Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 17720936, 25637381, 9240418, 10404063)
Color Diagnostics, LLC DBA Color Health RCV000222150 SCV000906530 uncertain significance Hereditary cancer-predisposing syndrome 2022-12-15 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 323 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). Functional studies in yeast showed this variant may have partial reduction in mismatch repair activity, with normal binding functions to other protein partners (PMID: 17720936). 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 an individual affected with Lynch syndrome (PMID: 9240418, 10404063). This variant has been identified in 3/282858 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.
Myriad Genetics, Inc. RCV000412467 SCV004018325 likely benign Lynch syndrome 1 2023-12-19 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: 27363726].
All of Us Research Program, National Institutes of Health RCV003997184 SCV004824487 uncertain significance Lynch syndrome 2023-06-26 criteria provided, single submitter clinical testing This missense variant replaces serine with cysteine at codon 323 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). Splice site prediction tools suggest that this variant may not impact RNA splicing. Functional studies showed this variant may have partial reduction in mismatch repair (MMR) activity, with normal binding functions to other protein partners (PMID: 17720936), but expression in haploid cells resulted in normal susceptibility to a DNA damaging agent (PMID: 33357406). This variant has been reported in an individual affected with Lynch syndrome (PMID: 10404063, 9240418). This variant has been identified in 3/282858 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.
CSER _CC_NCGL, University of Washington RCV000148634 SCV000190349 uncertain significance Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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