ClinVar Miner

Submissions for variant NM_002439.5(MSH3):c.2917A>G (p.Ile973Val)

gnomAD frequency: 0.00001  dbSNP: rs762608251
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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 RCV000804100 SCV000943994 uncertain significance not provided 2025-01-06 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 973 of the MSH3 protein (p.Ile973Val). This variant is present in population databases (rs762608251, gnomAD 0.005%). 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: 649217). 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 RCV001016927 SCV001177934 uncertain significance Hereditary cancer-predisposing syndrome 2023-06-17 criteria provided, single submitter clinical testing The p.I973V variant (also known as c.2917A>G), located in coding exon 21 of the MSH3 gene, results from an A to G substitution at nucleotide position 2917. The isoleucine at codon 973 is replaced by valine, an amino acid with highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Sema4, Sema4 RCV001016927 SCV002536094 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-15 criteria provided, single submitter curation
PreventionGenetics, part of Exact Sciences RCV003392609 SCV004120465 uncertain significance MSH3-related disorder 2023-06-13 criteria provided, single submitter clinical testing The MSH3 c.2917A>G variant is predicted to result in the amino acid substitution p.Ile973Val. This variant was reported in an individual with breast cancer from a large cohort study; however, no additional evidence was provided to support causation (Sandoval et al. 2021. PubMed ID: 33606809. Table S4). This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-80150052-A-G). This variant is interpreted as uncertain significance in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/649217). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.

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