ClinVar Miner

Submissions for variant NM_002439.5(MSH3):c.1778G>A (p.Arg593Gln)

gnomAD frequency: 0.00001  dbSNP: rs764832633
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000799438 SCV000939100 uncertain significance not provided 2025-02-03 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 593 of the MSH3 protein (p.Arg593Gln). This variant is present in population databases (rs764832633, gnomAD 0.009%). 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: 645380). 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 RCV001013146 SCV001173691 uncertain significance Hereditary cancer-predisposing syndrome 2024-03-13 criteria provided, single submitter clinical testing The p.R593Q variant (also known as c.1778G>A), located in coding exon 13 of the MSH3 gene, results from a G to A substitution at nucleotide position 1778. The arginine at codon 593 is replaced by glutamine, an amino acid with highly similar properties. This alteration was identified in a patient meeting testing criteria for HBOC (Chrysafi P et al. Cancers (Basel), 2023 Dec;15). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, the clinical significance of this alteration remains unclear.
Sema4, Sema4 RCV001013146 SCV002535984 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-16 criteria provided, single submitter curation
GeneDx RCV000799438 SCV002770029 uncertain significance not provided 2024-10-31 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Observed in a patient with breast and colon cancer (PMID: 35475445); This variant is associated with the following publications: (PMID: 39049123, 35475445)
St. Jude Molecular Pathology, St. Jude Children's Research Hospital RCV003153840 SCV003843117 uncertain significance Familial adenomatous polyposis 4 2022-10-17 criteria provided, single submitter clinical testing The MSH3 c.1778G>A (p.Arg593Gln) missense change has a maximum subpopulation frequency of 0.0062% in gnomAD v2.1.1 (https://gnomad.broadinstitute.org/). The in silico tool REVEL predicts a deleterious effect on protein function, but to our knowledge this prediction has not been confirmed by functional studies. This variant has been reported in at least one individual with colon cancer (PMID: 35475445). 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.
Baylor Genetics RCV003461117 SCV004197049 uncertain significance Endometrial carcinoma 2024-02-01 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV005036159 SCV005666192 uncertain significance Endometrial carcinoma; Familial adenomatous polyposis 4 2024-02-15 criteria provided, single submitter clinical testing

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