ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.2673C>G (p.Ile891Met)

gnomAD frequency: 0.00001  dbSNP: rs146006741
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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000215122 SCV000279264 uncertain significance not provided 2023-11-30 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 in a patient with hereditary breast cancer who also harbored a pathogenic variant in BRCA1 (PMID: 32547938); This variant is associated with the following publications: (PMID: 23621914, 17531815, 21120944, 32547938)
Labcorp Genetics (formerly Invitae), Labcorp RCV000473265 SCV000551150 benign Hereditary nonpolyposis colorectal neoplasms 2023-10-15 criteria provided, single submitter clinical testing
Ambry Genetics RCV001016279 SCV001177217 uncertain significance Hereditary cancer-predisposing syndrome 2023-07-26 criteria provided, single submitter clinical testing The p.I891M variant (also known as c.2673C>G), located in coding exon 4 of the MSH6 gene, results from a C to G substitution at nucleotide position 2673. The isoleucine at codon 891 is replaced by methionine, an amino acid with highly similar properties. This amino acid position is poorly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
All of Us Research Program, National Institutes of Health RCV003998617 SCV004838460 uncertain significance Lynch syndrome 2023-08-08 criteria provided, single submitter clinical testing This missense variant replaces isoleucine with methionine at codon 891 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 2/250540 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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