ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1963G>A (p.Val655Ile) (rs549467183)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000662941 SCV000807673 uncertain significance Lynch syndrome I 2018-06-13 reviewed by expert panel curation MLH1 methylation, but tumour with all proteins absent by IHC, proficient in CIMRA
GeneDx RCV000115514 SCV000149423 likely benign not provided 2021-04-05 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 26845104, 28767289, 25186627, 30212499, 30262796, 33294277, 32659497, 31569399)
University of Washington Department of Laboratory Medicine, University of Washington RCV000210146 SCV000266196 uncertain significance Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
Ambry Genetics RCV000217714 SCV000273748 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV001080304 SCV000284129 benign Hereditary nonpolyposis colorectal neoplasms 2020-12-03 criteria provided, single submitter clinical testing
Counsyl RCV000662941 SCV000785899 likely benign Lynch syndrome I 2018-01-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000115514 SCV000806017 likely benign not provided 2017-05-10 criteria provided, single submitter clinical testing
Color Health, Inc RCV000217714 SCV000903533 benign Hereditary cancer-predisposing syndrome 2017-09-14 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000780441 SCV000917691 likely benign not specified 2019-08-26 criteria provided, single submitter clinical testing Variant summary: MSH2 c.1963G>A (p.Val655Ile) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 251324 control chromosomes, predominantly at a frequency of 0.00075 within the Latino subpopulation in the gnomAD database. The observed variant frequency within Latino control individuals in the gnomAD database is approximately 1.32 fold of the estimated maximal expected allele frequency for a pathogenic variant in MSH2 causing Lynch Syndrome phenotype (0.00057), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Latino origin. c.1963G>A has been reported in the literature in sequencing studies among individuals affected with breast, colorectal and pancreatic cancers (example, Shirts_2016, Tung_2015, Shindo_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variant(s) have been reported in the literature and at our laboratory (BRCA1 del exons 9-12, Tung_2015; ATM c.8264_8268delATAAG, p.Tyr2755fs*12, Internal testing data), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven clinical diagnostic laboratories and one expert panel (InSIGHT) have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple submitters have reported the variant with conflicting assessments (5 as benign/likely benign and 3 as a VUS). Based on the evidence outlined above, the variant was classified as likely benign.

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.