ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.2447A>G (p.Gln816Arg)

gnomAD frequency: 0.00001  dbSNP: rs768572053
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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000221679 SCV000273308 likely benign Hereditary cancer-predisposing syndrome 2023-05-12 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000985803 SCV001134355 uncertain significance not provided 2023-07-13 criteria provided, single submitter clinical testing In the published literature, this variant has been reported in individuals with breast cancer and in healthy controls (PMIDs: 29684080 (2018), 35449176 (2022), 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared/genes/MSH2)). A screening assay based on cell survival in response to 6-thioguanine treatment indicates this and other missense variants at this codon have neutral effects on DNA mismatch repair function (PMID: 33357406 (2021)). The frequency of this variant in the general population, 0.00025 (5/19954 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.
Color Diagnostics, LLC DBA Color Health RCV000221679 SCV001352951 uncertain significance Hereditary cancer-predisposing syndrome 2021-03-09 criteria provided, single submitter clinical testing This missense variant replaces glutamine with arginine at codon 816 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A function study has reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 29684080). This variant has been identified in 5/282692 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 RCV001236583 SCV001409315 benign Hereditary nonpolyposis colorectal neoplasms 2024-01-15 criteria provided, single submitter clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University RCV003153497 SCV003843384 benign Ovarian cancer 2022-01-01 criteria provided, single submitter clinical testing
All of Us Research Program, National Institutes of Health RCV003997783 SCV004834205 uncertain significance Lynch syndrome 2023-06-15 criteria provided, single submitter clinical testing This missense variant replaces glutamine with arginine at codon 816 of the MSH2 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A function study has reported that this variant does not impact MSH2 function in a 6-thioguanine sensitivity assay in haploid human cells (PMID: 33357406). This variant has been reported in an individual affected with breast cancer (PMID: 29684080). This variant has been identified in 5/282692 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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