ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.2319C>T (p.Leu773=) (rs63749895)

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Total submissions: 10
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074734 SCV000107943 likely benign Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability 0.001-0.049
Invitae RCV001082589 SCV000166219 benign Hereditary nonpolyposis colorectal neoplasms 2020-11-25 criteria provided, single submitter clinical testing
GeneDx RCV000212663 SCV000211356 benign not specified 2014-07-02 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 RCV000160722 SCV000216685 likely benign Hereditary cancer-predisposing syndrome 2015-05-26 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.
Counsyl RCV000411581 SCV000488251 likely benign Hereditary nonpolyposis colorectal cancer type 5 2016-02-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000160722 SCV000685279 benign Hereditary cancer-predisposing syndrome 2016-04-25 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000679224 SCV000805862 likely benign not provided 2017-10-20 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000679224 SCV000888253 likely benign not provided 2018-01-15 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000212663 SCV000919754 likely benign not specified 2018-08-09 criteria provided, single submitter clinical testing Variant summary: MSH6 c.2319C>T alters a non-conserved nucleotide resulting in a synonymous change. 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 8.7e-05 in 277028 control chromosomes from all ethnicities, but was observed most frequently in the Latino subpopulation at a frequency of 0.00026 . This frequency is ~2x more frequent than expected for a pathogenic variant in MSH6 causing Lynch Syndrome (0.0026 vs. 0.00014), suggesting the variant may be benign. c.2319C>T has been reported in the literature in individuals affected with Lynch Syndrome and other cancers. In one family with four affected members, the variant was found only in the proband, showing a lack of segregation with disease and suggesting the variant is unlikely to be the cause of disease in this family (de Abajo_2005). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as benign (2x) or likely benign (2x). Based on the evidence outlined above, the variant was classified as likely benign.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000679224 SCV001747258 likely benign not provided 2021-06-01 criteria provided, single submitter clinical testing

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