Submissions for variant NM_000179.3(MSH6):c.1729C>T (p.Arg577Cys)

gnomAD frequency: 0.00010  dbSNP: rs542838372

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115381	SCV000149290	uncertain significance	not provided	2023-09-07	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 26333163, 18809606, 25133505, 26689913, 29659569, 27535533, 21120944, 17531815, 33008098, 33471991, 36243179, 35449176)
Counsyl	RCV000409690	SCV000487932	uncertain significance	Lynch syndrome 5	2015-12-08	criteria provided, single submitter	clinical testing
Invitae	RCV000524118	SCV000551178	benign	Hereditary nonpolyposis colorectal neoplasms	2024-01-24	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000491847	SCV000580218	likely benign	Hereditary cancer-predisposing syndrome	2023-09-01	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.
Color Diagnostics, LLC DBA Color Health	RCV000491847	SCV000685222	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 577 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with prostate (PMID: 29659569), ovarian (PMID: 33008098), breast (PMID: 33471991) and colorectal cancer (PMID: 18809606, 25133505). This variant has also been observed in healthy individuals in breast and pancreatic cancer case-control studies (PMID: 32980694, 33471991). This variant has been identified in 10/281608 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Mendelics	RCV003993789	SCV000837885	likely benign	Hereditary nonpolyposis colon cancer	2024-04-09	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000115381	SCV000888249	uncertain significance	not provided	2017-09-25	criteria provided, single submitter	clinical testing
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV000115381	SCV002010115	uncertain significance	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000491847	SCV002535654	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-01	criteria provided, single submitter	curation
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003235029	SCV003934342	uncertain significance	not specified	2024-02-08	criteria provided, single submitter	clinical testing	Variant summary: MSH6 c.1729C>T (p.Arg577Cys) results in a non-conservative amino acid change located in the DNA mismatch repair protein MutS, connector domain (IPR007860) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 2.8e-05 in 250210 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1729C>T has been reported in the literature in an individual affected with MSI stable colorectal cancer and in an individual with colorectal cancer who met at least one of the revised Bethesda guidelines, as well as in individuals affected with other cancers within the Lynch Syndrome tumor spectrum, without strong evidence for causality (e.g.Hampel_2008, Loizidou_2014, Paulo_2018, Barbosa_2020). In a large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 9/60466 cases, and in 4/53461 controls (Dorling_2021 through LOVD). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Nonpolyposis Colorectal Cancer. 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: 32658311, 33008098, 18809606, 25133505, 29659569, 33471991). ClinVar contains an entry for this variant (Variation ID: 89218). Based on the evidence outlined above, the variant was classified as uncertain significance.
Myriad Genetics, Inc.	RCV000409690	SCV004019030	uncertain significance	Lynch syndrome 5	2023-03-29	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
Baylor Genetics	RCV003466935	SCV004195557	uncertain significance	Endometrial carcinoma	2024-03-28	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV003997068	SCV004837795	uncertain significance	Lynch syndrome	2024-01-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 577 of the MSH6 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with prostate (PMID: 29659569), ovarian (PMID: 33008098), breast (PMID: 33471991) and colorectal cancer (PMID: 18809606, 25133505). This variant has also been observed in healthy individuals in breast and pancreatic cancer case-control studies (PMID: 32980694, 33471991). This variant has been identified in 10/281608 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV003235029	SCV005090481	uncertain significance	not specified	2024-07-31	criteria provided, single submitter	clinical testing