ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2926C>T (p.Arg976Cys) (rs587782386)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131393 SCV000186369 likely pathogenic Hereditary cancer-predisposing syndrome 2017-03-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Structural Evidence,Other data supporting pathogenic classification
GeneDx RCV000212673 SCV000211304 uncertain significance not provided 2014-05-22 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2926C>T at the cDNA level, p.Arg976Cys (R976C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). Although this variant has not, to our knowledge, been published in the literature as pathogenic or benign, another variant at the same codon, MSH6 Arg976His, is classified as a variant of uncertain significance by the International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) (Thompson 2014). The aforementioned variant was observed in an individual with synchronous colon and kidney cancers and classified as pathogenic based on the observed pattern of microsatellite instability and the concurrent detection in the tumor of a MSH6 somatic nonsense variant (Plaschke 2002). In other studies, in vitro mismatch repair (MMR) assays demonstrated decreased, but not deficient, MMR activity and slightly decreased repair efficiency leading authors to classify MSH6 Arg976His as a variant of uncertain significance (Cyr 2008, Drost 2012). MSH6 Arg976Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Arg976Cys occurs at a position that is highly conserved through mammals and is located in domain IV of the MutS domain (Terui 2013). In addition, in silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether MSH6 Arg976Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000630013 SCV000750969 uncertain significance Hereditary nonpolyposis colon cancer 2017-10-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 976 of the MSH6 protein (p.Arg976Cys). The arginine residue is highly 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 disease. ClinVar contains an entry for this variant (Variation ID: 142327). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; 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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