Submissions for variant NM_000179.3(MSH6):c.3246G>T (p.Pro1082=)

dbSNP: rs3136351

Total submissions: 29

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT)	RCV000074825	SCV000108036	benign	Lynch syndrome 1	2018-06-13	reviewed by expert panel	curation	Multifactorial likelihood analysis posterior probability < 0.001 (0.00065)
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000035323	SCV000058971	likely benign	not specified	2011-08-02	criteria provided, single submitter	clinical testing	Pro1082Pro in exon 5 of MSH6: This variant has been reported in individuals wit h hereditary breast and colorectal cancer, and hereditary breast cancer (3 of 27 2 chromosomes, ~1%) and was absent from 332 control chromosomes (Wasielewski 201 0). It has also been reported in dbSNP with a frequency of about 1% (rs3136351) and as a polymorphism without frequency information in individuals with HNPCC, H NPCC-related tumors, and CRC (Wijnen 1999, Woods 2005, Kets 2006, Perez-Caborner o 2009). This variant is not expected to have clinical significance because it d oes not alter an amino acid residue and is not located near a splice junction.
Eurofins Ntd Llc (ga)	RCV000035323	SCV000110154	benign	not specified	2013-02-22	criteria provided, single submitter	clinical testing
GeneDx	RCV000035323	SCV000170360	benign	not specified	2013-11-01	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	RCV000126832	SCV000212729	likely benign	Hereditary cancer-predisposing syndrome	2017-09-28	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.
Invitae	RCV001080525	SCV000252628	benign	Hereditary nonpolyposis colorectal neoplasms	2024-02-01	criteria provided, single submitter	clinical testing
PreventionGenetics, part of Exact Sciences	RCV000035323	SCV000302875	benign	not specified		criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000126832	SCV000537401	benign	Hereditary cancer-predisposing syndrome	2015-03-31	criteria provided, single submitter	clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	RCV000614249	SCV000744296	benign	Lynch syndrome 5	2015-09-21	criteria provided, single submitter	clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories	RCV000757474	SCV000885716	benign	not provided	2018-06-27	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000757474	SCV000888267	benign	not provided	2022-06-24	criteria provided, single submitter	clinical testing
Mendelics	RCV000614249	SCV001135835	likely benign	Lynch syndrome 5	2019-05-28	criteria provided, single submitter	clinical testing
CeGaT Center for Human Genetics Tuebingen	RCV000757474	SCV001152301	likely benign	not provided	2023-11-01	criteria provided, single submitter	clinical testing	MSH6: BP4, BP7, BS2
Illumina Laboratory Services, Illumina	RCV000614249	SCV001297509	benign	Lynch syndrome 5	2018-05-01	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). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario	RCV001798077	SCV002042047	likely benign	Breast and/or ovarian cancer	2022-03-21	criteria provided, single submitter	clinical testing
Genetic Services Laboratory, University of Chicago	RCV000035323	SCV002070931	benign	not specified	2021-11-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000126832	SCV002527991	benign	Hereditary cancer-predisposing syndrome	2020-07-14	criteria provided, single submitter	curation
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000035323	SCV002552333	benign	not specified	2023-08-15	criteria provided, single submitter	clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C.	RCV000126832	SCV004014933	benign	Hereditary cancer-predisposing syndrome	2023-03-21	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000614249	SCV004015999	likely benign	Lynch syndrome 5	2023-07-07	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000035323	SCV000257246	benign	not specified		no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000035323	SCV000592629	benign	not specified		no assertion criteria provided	clinical testing	The MSH6 p.Pro1082Pro variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. This variant was identified in the literature in 5 of 1364 proband chromosomes (frequency: 0.004) from individuals with colorectal cancer or Lynch Syndrome-related tumours but was not identified in 170 control chromosomes from these studies (Kets 2006, Kolodner 1999, Pastrello 2011, Perez-Cabornero 2009, Woods 2005). The variant was also identified in the following databases: “InSiGHT Colon Cancer Database”, COSMIC, “MisMatch Repair Variants Database”, dbSNP (ID: rs3136351) “With probable-non-pathogenic allele”, and UMD (15X as a likely neutral variant). In UMD it was reported to co-occur with a pathogenic mutation in the MLH1 gene (MLH1 c.518T>G (p.Leu173Arg)), increasing the likelihood that the MSH6 p.Val1082Val variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 5 of 2500 chromosomes (frequency: 0.002), Exome Variant Server project in 46 of 8600 European American and in 5 of 4406 African American alleles, the Exome Aggregation Consortium (ExAC) database (released Oct 20th, 2014) in 424 of 122862 chromosomes (frequency: 0.003) from a population of European (Non-Finnish)/East Asian/Other/African/Latino/South Asian/European (Finnish) individuals, increasing the likelihood this could be a low frequency benign variant. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000614249	SCV000734218	likely benign	Lynch syndrome 5		no assertion criteria provided	clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center	RCV000614249	SCV000745653	likely benign	Lynch syndrome 5	2015-05-13	no assertion criteria provided	clinical testing
True Health Diagnostics	RCV000126832	SCV000788048	likely benign	Hereditary cancer-predisposing syndrome	2017-11-10	no assertion criteria provided	clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	RCV000035323	SCV001800479	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics, Academic Medical Center	RCV000035323	SCV001921820	benign	not specified		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000035323	SCV001957947	benign	not specified		no assertion criteria provided	clinical testing
Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute	RCV000035323	SCV001977633	benign	not specified		no assertion criteria provided	clinical testing