ClinVar Miner

Submissions for variant NM_002439.5(MSH3):c.3341A>G (p.His1114Arg)

gnomAD frequency: 0.00001  dbSNP: rs1158289237
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV001020041 SCV001181465 likely benign Hereditary cancer-predisposing syndrome 2024-03-07 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.
Labcorp Genetics (formerly Invitae), Labcorp RCV001060601 SCV001225301 uncertain significance not provided 2025-02-03 criteria provided, single submitter clinical testing This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 1114 of the MSH3 protein (p.His1114Arg). This variant is present in population databases (no rsID available, gnomAD 0.004%). This variant has not been reported in the literature in individuals affected with MSH3-related conditions. ClinVar contains an entry for this variant (Variation ID: 823636). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003230277 SCV003928033 uncertain significance Familial adenomatous polyposis 4 2023-05-03 criteria provided, single submitter clinical testing The MSH3 c.3341A>G (p.His1114Arg) missense change has a maximum subpopulation frequency of 0.006% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a benign effect of this variant on protein function, and to our knowledge functional studies have not been performed. To our knowledge, this variant has not been reported in individuals with MSH3-associated familial adenomatous polyposis. In summary, the evidence currently available is insufficient to determine the clinical significance of this variant. It has therefore been classified as of uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001060601 SCV005623841 uncertain significance not provided 2024-09-28 criteria provided, single submitter clinical testing The MSH3 c.3341A>G (p.His1114Arg) variant has not been reported in individuals with MSH3-related conditions in the published literature. The frequency of this variant in the general population, 0.000044 (5/113492 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.

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