ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1666T>C (p.Leu556=) (rs61756466)

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Total submissions: 18
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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: 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 2020-12-08 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000202289 SCV000303159 benign not specified criteria provided, single submitter clinical testing
Color Health, Inc 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
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000625239 SCV000744276 benign Lynch syndrome I 2015-09-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000625239 SCV000745641 likely benign Lynch syndrome I 2015-07-21 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000202289 SCV000859733 benign not specified 2018-03-07 criteria provided, single submitter clinical testing
Mendelics RCV000625239 SCV001135739 likely benign Lynch syndrome I 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV001092633 SCV001249234 likely benign not provided 2020-01-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000625239 SCV001297154 likely benign Lynch syndrome I 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.
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

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