ClinVar Miner

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

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Total submissions: 12
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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 RCV001284654 SCV000149442 likely benign not provided 2021-01-22 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 17720936, 12124176, 8872463, 26951660, 28125613, 25637381, 18781619, 20672385, 17192056, 15340264, 11870161, 18822302, 22102614, 22949387, 20176959, 11606497, 25980754, 18383312, 17250665, 17594722, 23741719, 19464205, 26333163, 22045683, 27601186, 31159747, 31237724, 31569399)
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 colorectal neoplasms 2020-11-24 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115533 SCV000690113 likely benign Hereditary cancer-predisposing syndrome 2016-03-10 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000200986 SCV000696272 benign not specified 2021-06-26 criteria provided, single submitter clinical testing Variant summary: MSH2 c.499G>C (p.Asp167His) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.7e-05 in 251484 control chromosomes in the gnomAD database, including 1 homozygote. This frequency is not higher than expected for a pathogenic variant in MSH2 causing Hereditary Nonpolyposis Colorectal Cancer (8.7e-05 vs 0.00057), allowing no conclusion about variant significance. c.499G>C has been reported in the literature in individuals affected with Hereditary Nonpolyposis Colorectal Cancer and breast cancer (e.g. Moslein_1996, Scartozzi_2002, Belvederesi_2008, Yurgelun_2015, Lagerstedt-Robinson_2016, Rizzolo_2019, Tsaousis_2019, Ryan_2020, Doling_2021) but it was also reported in controls (e.g. Dorling_2021). In two of the patients from these studies where tumor analysis was carried out, IHC was found to be normal for MSH2 while loss of MLH1 protein expression was noted (Scartozzi_2002, Belvederesi_2008). In a third patient who did not fullfil Amsterdam-II Criteria or Revised Bethesda Criteria, normal IHC results and MSS was observed (Ryan_2020). These results provide supporting evidence for a benign role of the variant. Co-occurrences with pathogenic variants have been reported [MLH1 c.1852_1854delAAG, p.Lys618del (UMD); MLH1 21delG, p.Ile8PhefsX9 (Moslein_1996)], providing further supporting evidence for a benign role. Experimental evidence from multiple studies, including a recent in cellulo functional assay utilizing CRISPR-Cas9 gene editing in human embryonic stem cells, agree in their majority that the variant acts comparable to wild type (e.g. Gammie_2007, Belvederesi_2008, Drost_2011, Rath_2019). Six ClinVar submitters including an expert panel (InSiGHT) (evaluation after 2014) cite the variant as benign/likely benign and three ClinVar submitters (evaluation after 2014) cite it as uncertain significance. Based on the evidence outlined above, the variant was classified as 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV001284654 SCV001470554 uncertain significance not provided 2020-05-25 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000148629 SCV000190344 likely benign Colorectal cancer, non-polyposis 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001284654 SCV001554252 uncertain significance not provided no assertion criteria provided clinical testing

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