ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2384T>C (p.Ile795Thr) (rs202127474)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000160681 SCV000214998 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000160681 SCV000902755 likely benign Hereditary cancer-predisposing syndrome 2017-06-22 criteria provided, single submitter clinical testing
Counsyl RCV000412250 SCV000488581 uncertain significance Hereditary nonpolyposis colorectal cancer type 5 2016-05-03 criteria provided, single submitter clinical testing
GeneDx RCV000588994 SCV000211296 uncertain significance not provided 2018-06-19 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.2384T>C at the cDNA level, p.Ile795Thr (I795T) at the protein level, and results in the change of an Isoleucine to a Threonine (ATA>ACA). Although this variant has not, to our knowledge, been published in the literature as a germline variant, MSH6 Ile795Thr has been reported as a somatic variant in a microsatellite stable serous endometrial tumor (Le Gallo 2012, Price 2013). MSH6 Ile795Thr was observed with an allele frequency of 0.19% (57/30782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the Lever 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 Ile795Thr is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588994 SCV000695811 uncertain significance not provided 2016-07-11 criteria provided, single submitter clinical testing variant summary: The MSH6 c.2384T>C (p.Ile795Thr) variant involves the alteration of a conserved nucleotide. 4/4 in silico tools predict a damaging outcome for this variant (SNPs&GO not captured due to low reliability index). 5/5 splice prediction tools predict no significant impact on normal splicing. ESE finder predicts that this variant may affect multiple ESE sites. However, these predictions have yet to be confirmed by functional studies. This variant was found in 38/121196 control chromosomes, predominantly observed in the South Asian subpopulation at a frequency of 0.0020604 (34/16502). This frequency is about 15 times the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421), suggesting this is likely a benign polymorphism found primarily in the populations of South Asian origin. This variant also has been reported in one serous endometrial tumor sample with stable microsatellite markers. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS-possibly benign.
Invitae RCV000122957 SCV000166220 likely benign Hereditary nonpolyposis colon cancer 2017-12-14 criteria provided, single submitter clinical testing
Pathway Genomics RCV000172814 SCV000223780 uncertain significance Lynch syndrome I 2014-10-30 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212664 SCV000601530 uncertain significance not specified 2016-11-29 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.