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

dbSNP: rs267607919

Total submissions: 14

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	RCV000679309	SCV000149432	likely benign	not provided	2020-09-16	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 12373605, 10495924, 15872200, 11546830, 11879922, 25111426, 18561205, 23729658)
Ambry Genetics	RCV000115523	SCV000186646	likely benign	Hereditary cancer-predisposing syndrome	2018-12-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Invitae	RCV001080253	SCV000255275	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000115523	SCV000685074	likely benign	Hereditary cancer-predisposing syndrome	2021-12-14	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	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	2023-08-11	criteria provided, single submitter	clinical testing
Mendelics	RCV000986647	SCV001135695	benign	Lynch syndrome 1	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.
Sema4, Sema4	RCV000115523	SCV002534504	likely benign	Hereditary cancer-predisposing syndrome	2021-06-17	criteria provided, single submitter	curation
Fulgent Genetics, Fulgent Genetics	RCV002504986	SCV002805448	likely benign	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-03-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000417384	SCV004025221	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000115523	SCV004228077	benign	Hereditary cancer-predisposing syndrome	2024-01-04	criteria provided, single submitter	clinical testing