ClinVar Miner

Submissions for variant NM_000179.2(MSH6):c.3439-2A>G (rs267608098)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000508266 SCV000604276 pathogenic not specified 2016-12-13 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130487 SCV000185356 pathogenic Hereditary cancer-predisposing syndrome 2017-09-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Functionally-validated splicing mutation,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Alterations at the canonical donor/acceptor sites (+/- 1, 2) without other strong (b-level) evidence supporting pathogenicity
Color RCV000130487 SCV000537629 likely pathogenic Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing
Counsyl RCV000576575 SCV000677748 likely pathogenic Hereditary nonpolyposis colorectal cancer type 5 2017-01-04 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000074859 SCV000592642 pathogenic Lynch syndrome criteria provided, single submitter clinical testing
GeneDx RCV000202159 SCV000279108 pathogenic not provided 2018-07-02 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH6 c.3439-2A>G or IVS5-2A>G and consists of an A>G nucleotide substitution at the -2 position of intron 5 of the MSH6 gene. The variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. MSH6 c.3439-2A>G has been observed in individuals with personal and/or family history of Lynch-associated cancers and/or polyps and was found to cause loss of mismatch repair function (Kolodner 1999, Baglietto 2010, Yurgelun 2015, Haraldsdottir 2016). We consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000074859 SCV000695866 pathogenic Lynch syndrome 2016-01-04 criteria provided, single submitter clinical testing
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000074859 SCV000108071 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Invitae RCV000524176 SCV000253678 pathogenic Hereditary nonpolyposis colon cancer 2018-12-07 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 5 of the MSH6 gene. It is expected to disrupt RNA splicing and likely results in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals and families affected with Lynch syndrome-associated cancer and/or colorectal polyps (PMID: 10537275, 20028993, 25980754, Invitae). This variant is also known as IVS5-2A>G in the literature. ClinVar contains an entry for this variant (Variation ID: 89391). Donor and acceptor splice site variants typically lead to a loss of protein function (PMID: 16199547), and loss-of-function variants in MSH6 are known to be pathogenic (PMID: 24362816, 18269114). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000074859 SCV000271401 pathogenic Lynch syndrome 2016-03-29 criteria provided, single submitter clinical testing The c.3439-2A>G variant in MSH6 has been reported in 3 individuals with MSH6-ass ociated cancers (Kolodner 1999, Baglietto 2010) and was absent from large popula tion studies. This variant occurs in the invariant region (- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abno rmal or absent protein. Heterozygous loss-of-function of the MSH6 gene is an est ablished disease mechanism in individuals with Lynch syndrome. In addition, this variant was classified as Likely Pathogenic on September 5, 2013 by the ClinGen -approved InSiGHT expert panel (ClinVar SCV000108071.2). In summary, this varian t meets criteria to be classified as pathogenic for Lynch syndrome in an autosom al dominant manner based upon predicted impact to the protein, reports in multip le affected individuals and absence in controls.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202159 SCV000257254 pathogenic not provided 2018-02-23 no assertion criteria provided clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000202159 SCV000888274 pathogenic not provided 2018-04-11 criteria provided, single submitter clinical testing

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