ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.1675T>C (p.Cys559Arg)

dbSNP: rs1558662565
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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000758611 SCV000887367 uncertain significance Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH6 NM_000179.2:c.1675T>C has a 70.0% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH6 locus. See Shirts et al 2018, PMID 29887214.
Invitae RCV001244929 SCV001418185 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2020-08-28 criteria provided, single submitter clinical testing 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). This variant has not been reported in the literature in individuals with MSH6-related conditions. ClinVar contains an entry for this variant (Variation ID: 619538). This variant is not present in population databases (ExAC no frequency). This sequence change replaces cysteine with arginine at codon 559 of the MSH6 protein (p.Cys559Arg). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and arginine.
Ambry Genetics RCV002397527 SCV002712781 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-20 criteria provided, single submitter clinical testing The p.C559R variant (also known as c.1675T>C), located in coding exon 4 of the MSH6 gene, results from a T to C substitution at nucleotide position 1675. The cysteine at codon 559 is replaced by arginine, an amino acid with highly dissimilar properties. This amino acid position is well 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.

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