ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3787C>T (p.Arg1263Cys) (rs367912290)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000164843 SCV000215526 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Center for Human Genetics, Inc RCV000659897 SCV000781795 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
Color RCV000164843 SCV000911159 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing
Counsyl RCV000659897 SCV000786062 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2018-02-15 criteria provided, single submitter clinical testing
GeneDx RCV000485038 SCV000568016 uncertain significance not provided 2017-11-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3787C>T at the cDNA level, p.Arg1263Cys (R1263C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has not, to our knowledge, been published in the literature as either a germline variant. However, this variant has been reported as a somatic variant in a gastric adenocarcinoma (Chen 2015). MSH6 Arg1263Cys 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 Arg1263Cys is located in the ATPase domain (Warren 2007, Kansikas 2011). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available information, it is unclear whether MSH6 Arg1263Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074929 SCV000108142 uncertain significance Lynch syndrome 2013-09-05 reviewed by expert panel research Insufficient evidence
Invitae RCV000559935 SCV000624917 uncertain significance Hereditary nonpolyposis colon cancer 2018-06-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 1263 of the MSH6 protein (p.Arg1263Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs367912290, ExAC 0.02%). This variant has been reported in an individual affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 89461). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The cysteine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. However, an algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be disruptive (PMID: 23621914). 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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