ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1729C>T (p.Arg577Cys) (rs542838372)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000115381 SCV000149290 uncertain significance not provided 2018-02-28 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1729C>T at the cDNA level, p.Arg577Cys (R577C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been reported in an individual with MSI-low sigmoid colon cancer diagnosed at age 59 who did not have a family history of colon or endometrial cancer, in an individual with colon cancer diagnosed at age 49, and in an individual with leukemia (Hampel 2008, Loizidou 2014, Lu 2015). The International Society for Gastrointestinal Hereditary Tumours Incorporated (InSiGHT) classifies this variant as being of uncertain significance (Thompson 2014). MSH6 Arg577Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the Connector Domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether MSH6 Arg577Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000409690 SCV000487932 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2015-12-08 criteria provided, single submitter clinical testing
Invitae RCV000524118 SCV000551178 uncertain significance Hereditary nonpolyposis colon cancer 2019-01-01 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 577 of the MSH6 protein (p.Arg577Cys). 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 been observed in individuals with colorectal cancer and prostate cancer (PMID: 18809606, 25133505, 29659569), as well as in individuals in the Leiden Open-source Variation Database (PMID: 21520333) and the Universal Mutation Database (PMID: 23729658). In one of these individuals, a pathogenic allele was also identified in the MSH6 gene, which suggests that this c.1729C>T substitution in MSH6 was not the primary cause of disease in this individual. ClinVar contains an entry for this variant (Variation ID: 89218). 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 disruptive. An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 26333163). 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.
Ambry Genetics RCV000491847 SCV000580218 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000491847 SCV000685222 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-03 criteria provided, single submitter clinical testing
Mendelics RCV000074681 SCV000837885 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000115381 SCV000888249 uncertain significance not provided 2017-09-25 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.