Submissions for variant NM_000179.3(MSH6):c.3259C>A (p.Pro1087Thr)

dbSNP: rs63750998

Total submissions: 11

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131160	SCV000186104	benign	Hereditary cancer-predisposing syndrome	2021-05-07	criteria provided, single submitter	clinical testing	This alteration is classified as 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.
GeneDx	RCV000212679	SCV000211317	likely benign	not provided	2018-11-21	criteria provided, single submitter	clinical testing	This variant is associated with the following publications: (PMID: 24040339, 12019211, 22102614, 17594722, 10537275, 15354210, 23621914, 11900875, 21120944, 26333163)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001083021	SCV000219165	likely benign	Hereditary nonpolyposis colorectal neoplasms	2025-01-30	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131160	SCV000685376	benign	Hereditary cancer-predisposing syndrome	2023-02-27	criteria provided, single submitter	clinical testing
Illumina Laboratory Services, Illumina	RCV001137558	SCV001297510	uncertain significance	Lynch syndrome 5	2017-10-13	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.
Sema4, Sema4	RCV000131160	SCV002527994	uncertain significance	Hereditary cancer-predisposing syndrome	2021-05-28	criteria provided, single submitter	curation
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000212679	SCV002774193	likely benign	not provided	2023-03-06	criteria provided, single submitter	clinical testing
Laboratory of Molecular Epidemiology of Birth Defects, West China Second University Hospital, Sichuan University	RCV003153343	SCV003843426	benign	Ovarian cancer	2022-01-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV001137558	SCV004018630	likely benign	Lynch syndrome 5	2023-11-16	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: 27363726].
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV005357445	SCV005919346	likely benign	Mismatch repair cancer syndrome 3	2024-04-12	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV004537277	SCV004744600	uncertain significance	MSH6-related disorder	2024-02-09	no assertion criteria provided	clinical testing	The MSH6 c.3259C>A variant is predicted to result in the amino acid substitution p.Pro1087Thr. This variant was detected in an individual with a personal and family history of colorectal cancer (Kolodner et al. 1999. PubMed ID: 10537275). However, functional studies with recombinant MSH6 protein have indicated that dimerization with MSH2 and mismatch repair activity are not compromised by the p.Pro1087Thr variant (Kariola et al. 2002. PubMed ID: 12019211; Drost et al. 2012. PubMed ID: 22102614). This variant is documented in the gnomAD general population database with an allele frequency of ~0.04% among individuals of South Asian descent. In ClinVar, this variant has conflicting interpretations including likely benign and variant of uncertain significance (https://www.ncbi.nlm.nih.gov/clinvar/variation/89359/). However, at this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.