ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2342C>T (p.Pro781Leu) (rs1553413710)

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
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000502336 SCV000592606 uncertain significance not specified 2012-11-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589271 SCV000695808 uncertain significance not provided 2017-03-03 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.2342C>T (p.Pro781Leu) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution. The variant is found within the functional core domain of the protein (InterPro) and 4/4 in silico tools predict a damaging outcome (SNPs&GO not captured due to low reliability index). This variant is absent from the large control population database ExAC (0/121254 control chromosomes). To our knowledge, the variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a variant of uncertain significance (VUS) until additional information becomes available.
University of Washington Department of Laboratory Medicine,University of Washington RCV000664307 SCV000788239 pathogenic Lynch syndrome 2018-04-01 criteria provided, single submitter research The MSH6 gene variant designated as NM_000179.2:c.2342C>T (p.Pro781Leu) is classified as pathogenic. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 1.22 to 1, providing some evidence for pathogenicity (Thompson et al., 2003, PMID:2900794). Using computer predictions from MAPP and Polyphen2 algorithms we estimated a pretest probability of 90% supporting pathogenicity (Thompson et al, 2013, PMID:22949379). Combining pretest probability and segregation likelihood gives 92% probability of pathogenicity. In addition, this patient’s tumor had microsatellite instability and loss of MSH6, providing further evidence for pathogenicity. Bayesian analysis integrating all data (Tavtigian et al, 2018, PMID:29300386) gives over 99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is predicted to alter MSH6 function and cause Lynch syndrome-associated cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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.