ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2300C>G (p.Thr767Ser) (rs587781462)

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
GeneDx RCV000483534 SCV000566848 uncertain significance not specified 2017-05-09 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2300C>G at the cDNA level, p.Thr767Ser (T767S) at the protein level, and results in the change of a Threonine to a Serine (ACT>AGT). This variant has been observed in at least one individual with colon cancer and a family history of colon cancer (Zhang 2015). This family was also found to carry a pathogenic MLH1 variant. In addition, this variant showed incomplete segregation with cancer (Zhang 2015). MSH6 Thr767Ser 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 Threonine and Serine share similar properties, this is considered a conservative amino acid substitution. MSH6 Thr767Ser occurs at a position that is conserved across species and is located in domain III of the MutS domain (Terui 2013). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether MSH6 Thr767Ser is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000542142 SCV000624744 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-11-08 criteria provided, single submitter clinical testing This sequence change replaces threonine with serine at codon 767 of the MSH6 protein (p.Thr767Ser). The threonine residue is highly conserved and there is a small physicochemical difference between threonine and serine. This variant is present in population databases (rs587781462, ExAC 0.01%). This variant has been observed in an individual affected with Lynch syndrome (PMID: 29212164). This variant has also been observed in a family with colorectal cancer (PMID: 25892863). However, in that family a pathogenic allele was also identified in MLH1, which suggests that this c.2300C>G variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 419197). 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, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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.
Color RCV000580933 SCV000685278 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-22 criteria provided, single submitter clinical testing
Counsyl RCV000662407 SCV000784830 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-12-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000765686 SCV000897028 uncertain significance Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2018-10-31 criteria provided, single submitter clinical testing
Ambry Genetics RCV000580933 SCV001175918 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-13 criteria provided, single submitter clinical testing Insufficient evidence

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.