ClinVar Miner

Submissions for variant NM_002439.5(MSH3):c.1361G>A (p.Arg454Gln)

gnomAD frequency: 0.00004  dbSNP: rs144798521
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000805983 SCV000945961 uncertain significance not provided 2022-11-01 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 454 of the MSH3 protein (p.Arg454Gln). This variant is present in population databases (rs144798521, gnomAD 0.1%). 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: 650766). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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.
Ambry Genetics RCV001011127 SCV001171414 likely benign Hereditary cancer-predisposing syndrome 2019-08-06 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.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000805983 SCV002010470 uncertain significance not provided 2021-11-03 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV001011127 SCV002535945 uncertain significance Hereditary cancer-predisposing syndrome 2021-06-16 criteria provided, single submitter curation
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000805983 SCV004221033 uncertain significance not provided 2023-07-10 criteria provided, single submitter clinical testing To the best of our knowledge, this variant has not been reported in individuals with MSH3-related conditions in the published literature. The frequency of this variant in the general population, 0.0011 (35/30610 chromosomes in South Asian subpopulation (Genome Aggregation Database, http://gnomad.broadinstitute.org)), is higher than would generally be expected for pathogenic variants in this gene. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded conflicting predictions that this variant is benign or damaging. Based on the available information, we are unable to determine the clinical significance of this variant.

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