ClinVar Miner

Submissions for variant NM_002439.5(MSH3):c.3188T>C (p.Ile1063Thr)

gnomAD frequency: 0.00010  dbSNP: rs758008315
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Labcorp Genetics (formerly Invitae), Labcorp RCV000806258 SCV000946247 uncertain significance not provided 2024-02-01 criteria provided, single submitter clinical testing This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 1063 of the MSH3 protein (p.Ile1063Thr). This variant is present in population databases (rs758008315, 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: 650997). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Not Available"; PolyPhen-2: "Benign"; Align-GVGD: "Not Available". The threonine amino acid residue is found in multiple mammalian species, which suggests that this missense change does not adversely affect protein function. 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 RCV001019052 SCV001180359 uncertain significance Hereditary cancer-predisposing syndrome 2023-02-21 criteria provided, single submitter clinical testing The p.I1063T variant (also known as c.3188T>C), located in coding exon 23 of the MSH3 gene, results from a T to C substitution at nucleotide position 3188. The isoleucine at codon 1063 is replaced by threonine, an amino acid with similar properties. This amino acid position is not well 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.
GeneDx RCV000806258 SCV002819026 uncertain significance not provided 2022-12-28 criteria provided, single submitter clinical testing Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
PreventionGenetics, part of Exact Sciences RCV003432771 SCV004117009 uncertain significance MSH3-related disorder 2023-01-27 criteria provided, single submitter clinical testing The MSH3 c.3188T>C variant is predicted to result in the amino acid substitution p.Ile1063Thr. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0085% of alleles in individuals of European (Non-Finnish) descent in gnomAD (http://gnomad.broadinstitute.org/variant/5-80168992-T-C) and interpreted as uncertain in ClinVar (https://www.ncbi.nlm.nih.gov/clinvar/variation/650997/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Baylor Genetics RCV003461158 SCV004196969 uncertain significance Endometrial carcinoma 2024-03-18 criteria provided, single submitter clinical testing

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