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

dbSNP: rs267607919

Total submissions: 15

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: seen in unaffected individuals, 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080253	SCV000255275	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-02-04	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
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	2025-03-04	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
Myriad Genetics, Inc.	RCV000986647	SCV005897144	benign	Lynch syndrome 1	2024-12-03	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 27363726]. This variant has been observed in trans with a known pathogenic variant in one or more individuals lacking clinical features consistent with gene-specific recessive disease.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005357490	SCV005921178	likely benign	Muir-Torré syndrome	2023-08-10	criteria provided, single submitter	clinical testing