ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1957G>A (p.Val653Met)

gnomAD frequency: 0.00001  dbSNP: rs768095444
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000222892 SCV000277711 uncertain significance Hereditary cancer-predisposing syndrome 2022-02-08 criteria provided, single submitter clinical testing The c.1957G>A (p.V653M) alteration is located in exon 4 (coding exon 4) of the MSH6 gene. This alteration results from a G to A substitution at nucleotide position 1957, causing the valine (V) at amino acid position 653 to be replaced by a methionine (M). Based on insufficient or conflicting evidence, the clinical significance of this alteration remains unclear.
GeneDx RCV000478131 SCV000569042 uncertain significance not provided 2023-06-05 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; Observed among both cases and controls in a breast cancer case-control study (Dorling et al., 2021); This variant is associated with the following publications: (PMID: 22949387, 17531815, 21120944, 29338072, 33471991)
Invitae RCV000629954 SCV000750910 benign Hereditary nonpolyposis colorectal neoplasms 2023-10-09 criteria provided, single submitter clinical testing
Sema4, Sema4 RCV000222892 SCV002535685 uncertain significance Hereditary cancer-predisposing syndrome 2021-09-25 criteria provided, single submitter curation
All of Us Research Program, National Institutes of Health RCV003998550 SCV004838170 uncertain significance Lynch syndrome 2023-08-15 criteria provided, single submitter clinical testing This missense variant replaces valine with methionine at codon 653 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 1/282590 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.

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