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: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000805983 SCV000945961 uncertain significance not provided 2024-12-12 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 missense change has been observed in individual(s) with breast cancer and colorectal cancer (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 650766). 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 disruptive. 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 2024-08-15 criteria provided, single submitter clinical testing The MSH3 c.1361G>A (p.Arg454Gln) variant has been reported in the published literature in an individual who met the criteria for hereditary breast and ovarian cancer or Lynch syndrome genetic (PMID: 38136308 (2023)). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV005231357 SCV005873209 uncertain significance not specified 2025-03-04 criteria provided, single submitter clinical testing

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