Submissions for variant NM_000251.3(MSH2):c.573C>T (p.Leu191=)

gnomAD frequency: 0.01972  dbSNP: rs1800151

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000076644	SCV000107679	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	MAF >1%
Ambry Genetics	RCV000162404	SCV000212734	benign	Hereditary cancer-predisposing syndrome	2014-11-18	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
PreventionGenetics, part of Exact Sciences	RCV000202058	SCV000303166	benign	not specified		criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000625238	SCV000430914	likely benign	Lynch syndrome 1	2018-01-23	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.
Invitae	RCV001082442	SCV000559177	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000759115	SCV000604264	benign	not provided	2023-09-21	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000162404	SCV000685101	benign	Hereditary cancer-predisposing syndrome	2015-04-13	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625238	SCV000744269	benign	Lynch syndrome 1	2015-09-21	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000202058	SCV000888224	benign	not specified	2021-03-31	criteria provided, single submitter	clinical testing
GeneDx	RCV000759115	SCV001906769	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000162404	SCV002534536	benign	Hereditary cancer-predisposing syndrome	2020-10-21	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202058	SCV002552199	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000162404	SCV004014876	benign	Hereditary cancer-predisposing syndrome	2023-01-24	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000625238	SCV004015934	benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV003492426	SCV004239289	benign	Breast and/or ovarian cancer	2022-07-12	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202058	SCV000257193	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000202058	SCV000592470	benign	not specified		no assertion criteria provided	clinical testing	The MSH2 p.Leu191= variant was identified in the following databases: dbSNP (ID: rs1800151) “With Benign allele”, ClinVar (classified benign, reviewed by an expert panel (2013); submitters benign by InSIGHT, Ambry Genetics, Prevention Genetics, Invitae, Quest Diagnostics Nichols Institute San Juan Capistrano, ARUP, and Mayo Clinic, and likely benign by Illumina), Clinvitae (3x), Cosmic (in numerous primary tissue type tumours), UMD-LSDB (7x as neutral, co-occurring with pathogenic variants MSH2 c.1_211del (p.Met1?) and MSH6 c.2150_2153delTCAG (p.Val717AlafsX18)), Insight Colon Cancer Gene Variant Database (3x class 1), Mismatch Repair Genes Variant Database (2x), Insight Hereditary Tumors Database (4x), and in control databases in 1690 (48 homozygous) of 277178 chromosomes at a frequency of 0.006 increasing the likelihood this could be a low frequency benign variant (Genome Aggregation Database Feb 27, 2017). Breakdown of the observations by population include African in 1576 of 24014 chromosomes (freq: 0.07), Other in 12 of 6462 chromosomes (freq: 0.002), Latino in 86 of 34420 chromosomes (freq: 0.002), European Non-Finnish in 12 of 126694 chromosomes (freq: 0.0001), and South Asian in 4 of 30782 chromosomes (freq: 0.0001), while not observed in the Ashkenazi Jewish, East Asian, and European Finnish populations. The variant was not identified in GeneInSight-COGR, MutDB, OR Zhejiang Colon Cancer Database. The p.Leu191= variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. In addition, in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information this variant meets our laboratory's criteria to be classified as benign.
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625238	SCV000745634	benign	Lynch syndrome 1	2016-04-06	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000202058	SCV001800277	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000202058	SCV001906394	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000202058	SCV001917800	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202058	SCV001954124	benign	not specified		no assertion criteria provided	clinical testing