ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.499G>C (p.Asp167His) (rs63750255)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076615 SCV000107651 benign Lynch syndrome I 2018-06-13 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability < 0.001 (0.000015)
GeneDx RCV000200986 SCV000149442 likely benign not specified 2017-09-28 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000115533 SCV000212799 likely benign Hereditary cancer-predisposing syndrome 2018-04-16 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Other data supporting benign classification
Invitae RCV000524411 SCV000218857 benign Hereditary nonpolyposis colon cancer 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000115533 SCV000690113 likely benign Hereditary cancer-predisposing syndrome 2016-03-10 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000200986 SCV000696272 likely benign not specified 2019-01-15 criteria provided, single submitter clinical testing Variant summary: MSH2 c.499G>C (p.Asp167His) results in a non-conservative amino acid change located in domain II, which connects domain I to the body of the MSH2 clamp (Heinen_2002). Five of five in-silico tools predict a damaging effect of the variant on protein function, with multiple functional studies showing conflicting results (Belvederesi_2008, Drost_2011, Gammie_2007). The variant allele was found at a frequency of 8.3e-05 in 277216 control chromosomes, predominantly at a frequency of 0.00016 within the South Asian subpopulation in the gnomAD database, including 1 homozygotes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.499G>C has been reported in the literature in individuals affected with Lynch Syndrome (Belvederesi_2008, Moslein_1996, Scartozzi_2002, Yurgelun_2015, Lagerstedt-Robinson_2016). These reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variants have been reported (MLH1 c.1852_1854delAAG, p.Lys618del; MLH1 21delG, p.(Ile8Phefs*9)), providing supporting evidence for a benign role. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (benign/likely benign x5, VUS x1). Based on the evidence outlined above, the variant was classified as likely benign.
GeneKor MSA RCV000115533 SCV000822054 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Mendelics RCV000076615 SCV001135703 uncertain significance Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000076615 SCV001297030 likely benign Lynch syndrome I 2017-04-27 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
CSER _CC_NCGL, University of Washington RCV000148629 SCV000190344 likely benign Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research

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