ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.273TCT[2] (p.Leu94del) (rs267607919)

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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) RCV000076552 SCV000107578 no known pathogenicity Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability <0.001
GeneDx RCV000417384 SCV000149432 likely benign not specified 2017-09-20 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 RCV000115523 SCV000186646 likely benign Hereditary cancer-predisposing syndrome 2018-12-12 criteria provided, single submitter clinical testing Co-occurence with mutation in same gene (phase unknown);Other data supporting benign classification
Invitae RCV001080253 SCV000255275 likely benign Hereditary nonpolyposis colorectal neoplasms 2020-12-07 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115523 SCV000685074 likely benign Hereditary cancer-predisposing syndrome 2015-01-22 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679309 SCV000806037 likely benign not provided 2017-02-02 criteria provided, single submitter clinical testing
Mendelics RCV000076552 SCV000837817 benign Lynch syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679309 SCV000889432 benign not provided 2019-04-21 criteria provided, single submitter clinical testing
Mendelics RCV000986647 SCV001135695 benign Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000417384 SCV001360855 benign not specified 2019-04-23 criteria provided, single submitter clinical testing Variant summary: MSH2 c.279_281delTCT (p.Leu94del) results in an in-frame deletion that is predicted to remove one of three consecutive Leucine from the encoded protein. 5/5 computational tools predict no significant impact on normal splicing, which was confirmed by one ex vivo splicing assay (Tournier_2008). The variant allele was found at a frequency of 0.00018 in 282552 control chromosomes, predominantly at a frequency of 0.001 within the African or African-American subpopulation in the gnomAD database. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 2-folds higher than 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 African or African-American origin. c.279_281delTCT has been reported in the literature in individuals affected with CRC, HNPCC, and endometrial cancers (DeRycke_2017, Dymerska_2010, Geurts-Giele_2014, Gille_2002, Hampel_2005, Kurzawski_2006, Liu_2001) including one family that showed the variant to no segregate with disease (Liu_2001). Co-occurrence with other pathogenic variant has been reported (MSH2 c.638_639delTG, p.Leu213GlnfsX18), providing supporting evidence for a benign role. Seven ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) and an reputable database (InSiGHT) cite the variant as likely benign/benign. Based on the evidence outlined above, the variant was classified as benign.

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