ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3394G>C (p.Val1132Leu)

gnomAD frequency: 0.00001  dbSNP: rs781676597
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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 RCV000525940 SCV000624853 likely benign Hereditary nonpolyposis colorectal neoplasms 2024-11-28 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000579610 SCV000685396 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-27 criteria provided, single submitter clinical testing This missense variant replaces valine with leucine at codon 1132 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with MSH6-related disorders in the literature. This variant has been identified in 2/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Ambry Genetics RCV000579610 SCV001181629 uncertain significance Hereditary cancer-predisposing syndrome 2023-04-17 criteria provided, single submitter clinical testing The p.V1132L variant (also known as c.3394G>C), located in coding exon 5 of the MSH6 gene, results from a G to C substitution at nucleotide position 3394. The valine at codon 1132 is replaced by leucine, 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.
GeneDx RCV003225079 SCV003921495 uncertain significance not provided 2022-11-01 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; This variant is associated with the following publications: (PMID: 12019211, 17531815, 21120944)
All of Us Research Program, National Institutes of Health RCV004003691 SCV004835062 uncertain significance Lynch syndrome 2023-11-20 criteria provided, single submitter clinical testing This missense variant replaces valine with leucine at codon 1132 of the MSH6 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. To our knowledge, functional studies have not been performed for this variant. This variant has been reported in an individual affected with colorectal cancer with microsatellite stability and normal expression of MLH1, MSH2, MSH6 and PMS2 (www.umd.be). This variant has been identified in 2/282810 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Baylor Genetics RCV004568709 SCV005054987 uncertain significance Endometrial carcinoma 2023-12-24 criteria provided, single submitter clinical testing

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