ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2291C>A (p.Thr764Asn) (rs561198849)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000163700 SCV000214274 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-22 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000480884 SCV000568722 uncertain significance not provided 2017-12-07 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2291C>A at the cDNA level, p.Thr764Asn (T764N) at the protein level, and results in the change of a Threonine to an Asparagine (ACT>AAT). This variant was observed in at least one individual with colorectal cancer showing microsatellite instability and a family history meeting Amsterdam Criteria for Lynch syndrome; however, this individual also carried an MLH1 germline variant (Casey 2005). MSH6 Thr764Asn was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Threonine and Asparagine share similar properties, this is considered a conservative amino acid substitution. MSH6 Thr764Asn is located in the Lever domain (Warren 2007, Kansikas 2011). 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 Thr764Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000163700 SCV000685277 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-02 criteria provided, single submitter clinical testing
Invitae RCV000630065 SCV000751021 uncertain significance Hereditary nonpolyposis colon cancer 2019-11-13 criteria provided, single submitter clinical testing This sequence change replaces threonine with asparagine at codon 764 of the MSH6 protein (p.Thr764Asn). The threonine residue is weakly conserved and there is a small physicochemical difference between threonine and asparagine. This variant is present in population databases (rs561198849, ExAC 0.006%). This variant has been observed in an individua with Lynch syndrome (PMID: 15713769). However, in that individual a pathogenic allele was also identified in MLH1, which suggests that this c.2291C>A variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 184444). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be tolerated (PMID: 23621914). However, this prediction has not been confirmed by published functional studies and its 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.
Counsyl RCV000662379 SCV000784776 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-12-29 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000480884 SCV001134410 uncertain significance not provided 2019-08-20 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.