Submissions for variant NM_000179.3(MSH6):c.2319C>T (p.Leu773=)

gnomAD frequency: 0.00003  dbSNP: rs63749895

Total submissions: 12

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	2024-01-19	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	Lynch syndrome 5	2016-02-03	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000160722	SCV000685279	likely benign	Hereditary cancer-predisposing syndrome	2022-01-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	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 Center for Human Genetics Tuebingen	RCV000679224	SCV001747258	likely benign	not provided	2021-06-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000160722	SCV002535723	likely benign	Hereditary cancer-predisposing syndrome	2021-07-06	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000411581	SCV004019004	benign	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is considered benign. This variant is a silent/synonymous amino acid change and it is not expected to impact splicing.