ClinVar Miner

Submissions for variant NM_000179.3(MSH6):c.3246G>T (p.Pro1082=) (rs3136351)

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Total submissions: 23
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074825 SCV000108036 benign Lynch syndrome I 2018-06-13 reviewed by expert panel curation Multifactorial likelihood analysis posterior probability < 0.001 (0.00065)
Laboratory for Molecular Medicine, Partners HealthCare 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics 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 2020-12-04 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000035323 SCV000302875 benign not specified criteria provided, single submitter clinical testing
Color Health, Inc RCV000126832 SCV000537401 benign Hereditary cancer-predisposing syndrome 2015-03-31 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000035323 SCV000601566 likely benign not specified 2017-04-07 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000614249 SCV000744296 benign Hereditary nonpolyposis colorectal cancer type 5 2015-09-21 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, Amsterdam University Medical Center RCV000614249 SCV000745653 likely benign Hereditary nonpolyposis colorectal cancer type 5 2015-05-13 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 2018-04-14 criteria provided, single submitter clinical testing
Mendelics RCV000614249 SCV001135835 likely benign Hereditary nonpolyposis colorectal cancer type 5 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000757474 SCV001152301 likely benign not provided 2020-02-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000614249 SCV001297509 benign Hereditary nonpolyposis colorectal cancer type 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.
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 Hereditary nonpolyposis colorectal cancer type 5 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
Human Genetics - Radboudumc,Radboudumc RCV000035323 SCV001957947 benign not specified no assertion criteria provided clinical testing

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