ClinVar Miner

Submissions for variant NM_002439.5(MSH3):c.1721G>A (p.Arg574Gln)

gnomAD frequency: 0.00003  dbSNP: rs776668872
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000793121 SCV000932461 uncertain significance not provided 2023-11-24 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 574 of the MSH3 protein (p.Arg574Gln). This variant is present in population databases (rs776668872, gnomAD 0.003%). 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: 640155). 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 RCV001012851 SCV001173361 uncertain significance Hereditary cancer-predisposing syndrome 2024-02-07 criteria provided, single submitter clinical testing The p.R574Q variant (also known as c.1721G>A), located in coding exon 12 of the MSH3 gene, results from a G to A substitution at nucleotide position 1721. The arginine at codon 574 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV001543107 SCV001761614 uncertain significance Familial adenomatous polyposis 4 2021-07-15 criteria provided, single submitter clinical testing The MSH3 c.1721G>A (p.Arg574Gln) missense change has a maximum subpopulation frequency of 0.0029% in gnomAD v2.1.1 (PM2_supporting; https://gnomad.broadinstitute.org/variant/5-80040392-G-A). Six of six in silico tools predict a deleterious effect of this variant on protein function (PP3), but to our knowledge these predictions have not been confirmed by functional assays. This variant has been reported in an individual with non-small cell lung cancer (PMID: 31186761). In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_supporting, PP3.
Baylor Genetics RCV003467332 SCV004196947 uncertain significance Endometrial carcinoma 2023-10-31 criteria provided, single submitter clinical testing

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