ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3524C>T (p.Thr1175Ile) (rs369583604)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484936 SCV000572158 uncertain significance not provided 2017-07-07 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.3524C>T at the cDNA level, p.Thr1175Ile (T1175I) at the protein level, and results in the change of a Threonine to an Isoleucine (ACT>ATT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. MSH6 Thr1175Ile was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Threonine and Isoleucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. MSH6 Thr1175Ile occurs at a position that is conserved across species and is located within the ATPase domain (Kansikas 2011, Warren 2007). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether MSH6 Thr1175Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000573926 SCV000669934 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient evidence
Invitae RCV000706792 SCV000835862 uncertain significance Hereditary nonpolyposis colon cancer 2018-12-07 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 1175 of the MSH6 protein (p.Thr1175Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is present in population databases (rs369583604, ExAC 0.03%). This variant has not been reported in the literature in individuals with MSH6-related disease. ClinVar contains an entry for this variant (Variation ID: 422644). 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. 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.

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.