ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1216T>G (p.Cys406Gly) (rs1064794198)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000481662 SCV000568167 uncertain significance not provided 2016-10-17 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1216T>G at the cDNA level, p.Cys406Gly (C406G) at the protein level, and results in the change of a Cysteine to a Glycine (TGT>GGT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Cys406Gly was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Cysteine and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Cys406Gly occurs at a position that is conserved in mammals and is located in MutS domain I and an MSH2 binding site (Kariola 2002, Terui 2013). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Cys406Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000491552 SCV000580343 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-26 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color RCV000491552 SCV000690185 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-01 criteria provided, single submitter clinical testing
Invitae RCV000796619 SCV000936139 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces cysteine with glycine at codon 406 of the MSH6 protein (p.Cys406Gly). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 419942). 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 C0"). 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.

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