ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.97C>T (p.Arg33Cys) (rs730881811)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000160708 SCV000211338 uncertain significance not provided 2017-12-01 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.97C>T at the cDNA level, p.Arg33Cys (R33C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in a liver tumor (Walter 2017). MSH6 Arg33Cys was not observed at a significant frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg33Cys is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Arg33Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000490935 SCV000580233 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-25 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV001043688 SCV001207446 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-04-09 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 33 of the MSH6 protein (p.Arg33Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 182654). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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