ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.10C>T (p.Gln4Ter) (rs786201042)

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Total submissions: 13
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000162425 SCV000212772 pathogenic Hereditary cancer-predisposing syndrome 2018-03-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Invitae RCV000524100 SCV000253772 pathogenic Hereditary nonpolyposis colon cancer 2018-12-30 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln4*) in the MSH6 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant is a known common cause of Lynch syndrome in the French Canadian population of Quebec (PMID: 25318681, 20028993). This variant was found in approximately 1/400 newborns in this population, making it one of the most common Lynch syndrome variants described (PMID: 25318681). ClinVar contains an entry for this variant (Variation ID: 183723). Loss-of-function variants in MSH6 are known to be pathogenic (PMID: 18269114, 24362816). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine,University of Washington RCV000199142 SCV000266087 pathogenic Lynch syndrome 2015-11-20 criteria provided, single submitter clinical testing
GeneDx RCV000202232 SCV000279088 pathogenic not provided 2018-08-02 criteria provided, single submitter clinical testing This variant is denoted MSH6 c.10C>T at the cDNA level and p.Gln4Ter (Q4X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in individuals and families with suspected Lynch Syndrome and as a founder pathogenic variant in the French Canadian population (Baglietto 2010, Castellsagu? 2014, Yurgelun 2015, Shirts 2016, Yurgelun 2017). We consider this variant to be pathogenic.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000199142 SCV000592561 pathogenic Lynch syndrome 2014-08-21 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000515243 SCV000611207 pathogenic Endometrial carcinoma; Turcot syndrome; Hereditary nonpolyposis colorectal cancer type 5 2017-05-18 criteria provided, single submitter clinical testing
Color RCV000162425 SCV000685163 pathogenic Hereditary cancer-predisposing syndrome 2016-12-19 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000199142 SCV000731537 pathogenic Lynch syndrome 2017-03-01 criteria provided, single submitter clinical testing The p.Gln4X variant in MSH6 has been reported in >10 individuals with MSH6-assoc iated cancers, segregated with disease in at least 4 affected relatives from 3 f amilies (Baglietto 2010, Castellsague 2015, Yurgelun 2015), is present in ClinVa r (Variation ID# 183723), and was absent from large population studies. This non sense variant leads to a premature termination codon at position 4, which is pre dicted to lead to a truncated or absent protein. Heterozygous loss of function o f the MSH6 gene is an established disease mechanism in Lynch Syndrome. In summar y, this variant meets criteria to be classified as pathogenic for Lynch Syndrome in an autosomal dominant manner.
Center for Human Genetics, Inc RCV000202528 SCV000781779 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2016-11-01 criteria provided, single submitter clinical testing
Counsyl RCV000202528 SCV000785255 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-06-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000199142 SCV000919725 pathogenic Lynch syndrome 2017-10-06 criteria provided, single submitter clinical testing Variant summary: The MSH6 c.10C>T (p.Gln4X) variant results in a premature termination codon, predicted to cause a truncated or absent MSH6 protein due to nonsense mediated decay, which are commonly known mechanisms for disease. This variant was found in 5/270892 control chromosomes at a frequency of 0.0000185, which does not exceed the estimated maximal expected allele frequency of a pathogenic MSH6 variant (0.0001421). The variant has been reported to cosegregate in 11 French-Canadian families and was determined to be a founder mutation. One individual was homozygous for the variant and consistent with CMMR-D phenotype (Castellsague_2014). In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202232 SCV000257203 likely pathogenic not provided no assertion criteria provided research
OMIM RCV000202528 SCV000257496 pathogenic Hereditary nonpolyposis colorectal cancer type 5 2015-06-01 no assertion criteria provided literature only

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