ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.1844G>C (p.Cys615Ser) (rs730881793)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160673 SCV000580202 likely benign Hereditary cancer-predisposing syndrome 2017-01-18 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting benign classification,In silico models in agreement (benign),Rarity in general population databases (dbsnp, esp, 1000 genomes)
Color RCV000160673 SCV000903259 likely benign Hereditary cancer-predisposing syndrome 2016-04-28 criteria provided, single submitter clinical testing
Counsyl RCV000410091 SCV000488356 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-03-03 criteria provided, single submitter clinical testing
GeneDx RCV000212653 SCV000211284 uncertain significance not provided 2018-07-19 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.1844G>C at the cDNA level, p.Cys615Ser (C615S) at the protein level, and results in the change of a Cysteine to a Serine (TGT>TCT). This variant was observed in individuals with leukemia, breast, and ovarian cancer (Pal 2012, Tung 2015, Zhang 2015). MSH6 Cys615Ser was not observed at a significant allele frequency in large population cohorts (Lek 2016). MSH6 Cys615Ser is located in the connector domain (Warren 2007, Kansikas 2011). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether MSH6 Cys615Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Illumina Clinical Services Laboratory,Illumina RCV000304378 SCV000430964 uncertain significance Lynch syndrome 2016-06-14 criteria provided, single submitter clinical testing
Invitae RCV000524120 SCV000551194 uncertain significance Hereditary nonpolyposis colon cancer 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces cysteine with serine at codon 615 of the MSH6 protein (p.Cys615Ser). The cysteine residue is weakly conserved and there is a moderate physicochemical difference between cysteine and serine. This variant is present in population databases (rs730881793, ExAC 0.03%). This variant has been reported in an individual affected with ovarian cancer (PMID: 23047549), and an individual affected with breast cancer (PMID: 25186627). ClinVar contains an entry for this variant (Variation ID: 182628). 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 serine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Mendelics RCV000304378 SCV000837889 uncertain significance Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Vantari Genetics RCV000160673 SCV000267055 uncertain significance Hereditary cancer-predisposing syndrome 2016-02-05 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.