Submissions for variant NM_000251.3(MSH2):c.1666T>C (p.Leu556=)

gnomAD frequency: 0.00471  dbSNP: rs61756466

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000030242	SCV000107252	no known pathogenicity	Lynch syndrome	2013-09-05	reviewed by expert panel	research	Multifactorial likelihood analysis posterior probability <0.001
GeneDx	RCV000202289	SCV000170342	benign	not specified	2013-10-16	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	RCV000126816	SCV000212725	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.
Invitae	RCV000755303	SCV000262451	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000202289	SCV000303159	benign	not specified		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000126816	SCV000537394	benign	Hereditary cancer-predisposing syndrome	2015-04-06	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000202289	SCV000604252	benign	not specified	2019-02-21	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000625239	SCV000744276	benign	Lynch syndrome 1	2015-09-21	criteria provided, single submitter	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000625239	SCV000745641	likely benign	Lynch syndrome 1	2015-07-21	criteria provided, single submitter	clinical testing
Eurofins Ntd Llc (ga)	RCV000202289	SCV000859733	benign	not specified	2018-03-07	criteria provided, single submitter	clinical testing
Mendelics	RCV000625239	SCV001135739	likely benign	Lynch syndrome 1	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV001092633	SCV001249234	likely benign	not provided	2024-04-01	criteria provided, single submitter	clinical testing	MSH2: BP4, BP7, BS2
Illumina Laboratory Services, Illumina	RCV000625239	SCV001297154	likely benign	Lynch syndrome 1	2018-05-10	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.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798018	SCV002042096	benign	Breast and/or ovarian cancer	2023-05-25	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000202289	SCV002070920	benign	not specified	2021-03-18	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000126816	SCV002534392	benign	Hereditary cancer-predisposing syndrome	2020-05-27	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000202289	SCV002552236	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002490418	SCV002803010	likely benign	Lynch syndrome 1; Muir-Torré syndrome; Mismatch repair cancer syndrome 2	2022-03-18	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000625239	SCV004015941	benign	Lynch syndrome 1	2023-07-07	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000126816	SCV004228109	benign	Hereditary cancer-predisposing syndrome	2023-07-27	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000030242	SCV000052909	benign	Lynch syndrome	2013-04-22	no assertion criteria provided	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000202289	SCV000257149	benign	not specified		no assertion criteria provided	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353940	SCV000592515	benign	Carcinoma of colon		no assertion criteria provided	clinical testing	The p.Leu556Leu variant is not expected to have clinical significance because it does not alter an amino acid residue. It has been reported in the literature in 11/5116 proband chromosomes of individuals with either HNPCC or like-HNPCC. It was also identified in 1/340 control chromosomes. While some of the patients met either the strict Bethesda or Amsterdam criterias, others met only one of the guidelines or were missing some of the parameters within a particular criteria evaluated. (Auclair_2006, Hendriks_2003, Pastrello_2011, Scartozzi_2002, Tournier_2008, Wijnen_1995, Wehner_1997, Mangold_2005, Scott_2001). Of the one study where IHC results were available, MSH2 staining was normal in the patient with the variant (Hendriks_2003). Microsatellite status results were inconsistent with one paper citing low MSI in the variant positive tumor (Hendriks_2003), while another tumor exhibited high MSI (Pastrello_2011). The variant was also reported in the UMD (x23), InSiGHT Colon Cancer and Exome Server databases. The variant is listed in the dbSNP database as coming from a "clinical source" (ID#: rs61756466) with a MAF score of 0.003 (1000 Genomes), increasing the likelihood that this is a low frequency benign variant. Functional studies examining the effect of the variant on splicing reported that no aberrant splicing was detected (Auclair_2006, Tournier_2008). The identification of this variant in the presence of a second pathogenic variant increases the likelihood that this variant does not have clinical significance. In summary, based on the above information, this variant is classified as Benign.
True Health Diagnostics	RCV000126816	SCV000788031	likely benign	Hereditary cancer-predisposing syndrome	2018-01-12	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000202289	SCV001800268	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000202289	SCV001905720	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000202289	SCV001924113	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000202289	SCV001955814	benign	not specified		no assertion criteria provided	clinical testing