Submissions for variant NM_000179.3(MSH6):c.240A>G (p.Val80=)

gnomAD frequency: 0.00003  dbSNP: rs864622281

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001080007	SCV000259960	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-30	criteria provided, single submitter	clinical testing
Counsyl	RCV000410492	SCV000489318	likely benign	Lynch syndrome 5	2016-09-19	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000565482	SCV000669884	likely benign	Hereditary cancer-predisposing syndrome	2015-06-12	criteria provided, single submitter	clinical testing	This alteration is classified as likely 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000855621	SCV000695813	likely benign	not specified	2019-08-29	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000588097	SCV000805865	likely benign	not provided	2018-01-17	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV000410492	SCV001300594	uncertain significance	Lynch syndrome 5	2018-01-12	criteria provided, single submitter	clinical testing	This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score, this variant could not be ruled out of causing disease and therefore its association with disease required further investigation. A literature search was performed for the gene, cDNA change, and amino acid change (if applicable). No publications were found based on this search. This variant was therefore classified as a variant of unknown significance for this disease.
Color Diagnostics, LLC DBA Color Health	RCV000565482	SCV001347028	likely benign	Hereditary cancer-predisposing syndrome	2016-02-24	criteria provided, single submitter	clinical testing
GeneDx	RCV000588097	SCV001846891	benign	not provided	2015-03-03	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000588097	SCV002046357	likely benign	not provided	2023-06-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000410492	SCV004018912	benign	Lynch syndrome 5	2023-03-28	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.
All of Us Research Program, National Institutes of Health	RCV001354250	SCV004828614	likely benign	Lynch syndrome	2023-11-20	criteria provided, single submitter	clinical testing
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001354250	SCV001548814	uncertain significance	Lynch syndrome		no assertion criteria provided	clinical testing	The MSH6 p.Val80= variant was not identified in the literature nor was it identified in COGR, Cosmic, MutDB, UMD-LSDB, Zhejiang Colon Cancer Database, Mismatch Repair Genes Variant Database, and Insight Hereditary Tumors Database. The variant was identified in dbSNP (ID: rs864622281) as “With Likely benign allele”, in ClinVar (classified likely benign by Invitae, Counsyl and Ambry Genetics and uncertain significance by Laboratory Corporation of America), Clinvitae (2x) and the Genome Aggregation Database (Feb 27, 2017) in 2 of 30730 control chromosomes (frequency: 0.00007). It was observed in the following populations: African in 1 of 8664 chromosomes (frequency: 0.0001) and European Non-Finnish in 1 of 14844 chromosomes (frequency: 0.00007), but not in the Other, Latino, Ashkenazi Jewish, East Asian, Finnish and South Asian populations. The p.Val80= variant is not expected to have clinical significance because it does not result in a change of amino acid. The variant occurs outside of the splicing consensus sequence and 3 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. However, this information is not predictive enough to assume pathogenicity. This variant is classified as a variant of uncertain significance.