Submissions for variant NM_000179.3(MSH6):c.3478G>A (p.Val1160Ile)

gnomAD frequency: 0.00006  dbSNP: rs376799914

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165060	SCV000215761	likely benign	Hereditary cancer-predisposing syndrome	2020-07-24	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.
Invitae	RCV001082754	SCV000254316	likely benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-21	criteria provided, single submitter	clinical testing
GeneDx	RCV000656900	SCV000279109	likely benign	not provided	2019-09-09	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 23621914, 25503501, 27553368, 27878467)
Counsyl	RCV000410385	SCV000487884	uncertain significance	Lynch syndrome 5	2015-11-25	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000656900	SCV000805892	uncertain significance	not provided	2017-02-20	criteria provided, single submitter	clinical testing
Mendelics	RCV003323297	SCV000837916	benign	Hereditary nonpolyposis colon cancer	2023-08-22	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000656900	SCV000888275	likely benign	not provided	2020-01-16	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000165060	SCV000902810	likely benign	Hereditary cancer-predisposing syndrome	2015-06-09	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000201982	SCV000919736	uncertain significance	not specified	2023-05-22	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.3478G>A (p.Val1160Ile) results in a conservative amino acid change located in the C-terminal domain (IPR000432) found in proteins in the MutS family of DNA mismatch repair proteins. Three of five in-silico tools predict a benign effect of the variant on protein function. In addition, a bioinformatics tool developed to predict the impact of missense variants in MSH6, indicated no impact on protein function (Terui_2013). The variant allele was found at a frequency of 7.2e-05 in 251404 control chromosomes, predominantly at a frequency of 0.0012 within the Ashkenazi Jewish subpopulation in the gnomAD database. The observed variant frequency within Ashkenazi Jewish control individuals in the gnomAD database is approximately 8-fold higher than the expected maximum for a pathogenic variant in MSH6 causing Lynch Syndrome phenotype (0.00014), suggesting that the variant may be a benign polymorphism. c.3478G>A has been reported in the literature in individuals affected with Breast Cancer (Maxwell_2015, Pinto_2016, Yadav_2016, Guindalini_2022, McDonald_2022), however, these reports do not provide unequivocal conclusions about association of the variant with Lynch Syndrome. Co-occurrences with other pathogenic variants have been reported (BRCA1 c.2309C>A, p.Ser770X (Pinto 2016); BRCA2 c.5946delT, p.Ser1982ArgfsX22 (internal sample)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. The following publications have been ascertained in the context of this evaluation (PMID: 35264596, 25503501, 36315513, 27553368, 23621914, 27878467). Twelve submitters have provided clinical-significance assessments for this variant to ClinVar after 2014 and classified the variant as either likely benign (n=6) or VUS (n=6). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Illumina Laboratory Services, Illumina	RCV000410385	SCV001297512	uncertain significance	Lynch syndrome 5	2017-09-23	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. However, the evidence from the literature, in combination with allele frequency data from public databases where available, was not sufficient to rule this variant in or out of causing disease. Therefore, this variant is classified as a variant of unknown significance.
Baylor Genetics	RCV000410385	SCV001481268	uncertain significance	Lynch syndrome 5	2018-12-21	criteria provided, single submitter	clinical testing	This variant was determined to be of uncertain significance according to ACMG Guidelines, 2015 [PMID:25741868].
Genetic Services Laboratory, University of Chicago	RCV000201982	SCV002069374	uncertain significance	not specified	2018-08-01	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000165060	SCV002528034	likely benign	Hereditary cancer-predisposing syndrome	2021-12-29	criteria provided, single submitter	curation
Myriad Genetics, Inc.	RCV000410385	SCV004018875	likely benign	Lynch syndrome 5	2023-03-28	criteria provided, single submitter	clinical testing	This variant is considered likely benign. This variant is strongly associated with less severe personal and family histories of cancer, typical for individuals without pathogenic variants in this gene [PMID: 25085752].
Mayo Clinic Laboratories, Mayo Clinic	RCV000201982	SCV000257258	uncertain significance	not specified		no assertion criteria provided	research