ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3800T>C (p.Met1267Thr) (rs148445930)

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
Ambry Genetics RCV000132022 SCV000187081 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-08 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000230512 SCV000283823 uncertain significance Hereditary nonpolyposis colorectal neoplasms 2019-12-07 criteria provided, single submitter clinical testing This sequence change replaces methionine with threonine at codon 1267 of the MSH6 protein (p.Met1267Thr). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and threonine. This variant is present in population databases (rs148445930, ExAC 0.01%). This variant has been reported in individuals affected with colorectal cancer (PMID: 28135145). ClinVar contains an entry for this variant (Variation ID: 142672). An algorithm developed specifically for the MSH6 gene suggests that this missense change is likely to be deleterious (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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000508216 SCV000601586 uncertain significance not specified 2016-09-09 criteria provided, single submitter clinical testing
GeneDx RCV000589302 SCV000616792 uncertain significance not provided 2018-02-19 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3800T>C at the cDNA level, p.Met1267Thr (M1267T) at the protein level, and results in the change of a Methionine to a Threonine (ATG>ACG). This variant has been observed in two individuals with colorectal cancer (Yurgelun 2017). MSH6 Met1267Thr was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the ATPase 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 Met1267Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000132022 SCV000685445 uncertain significance Hereditary cancer-predisposing syndrome 2019-03-26 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000508216 SCV000695888 uncertain significance not specified 2020-07-10 criteria provided, single submitter clinical testing Variant summary: MSH6 c.3800T>C (p.Met1267Thr) results in a non-conservative amino acid change located in the C-terminal domain (IPR000432) of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8e-06 in 251200 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3800T>C has been reported in the literature in individuals affected with colorectal cancer and breast cancer (Yurgelun_2017, Wang_2019). These reports however, do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. Co-occurrence with another pathogenic variant has been reported (BRIP1 c.1066C>T, p.Arg356Ter), providing supporting evidence for a benign role (Wang_2019). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Counsyl RCV000662794 SCV000785607 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2017-10-02 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.