ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.942+3A>T (rs193922376)

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Total submissions: 19
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000030256 SCV000107794 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Multifactorial likelihood analysis posterior probability >0.99. Variant causes in-frame splicing aberration which interrupts know functional domains
Integrated Genetics/Laboratory Corporation of America RCV000030256 SCV000052923 pathogenic Lynch syndrome 2011-08-18 criteria provided, single submitter curation Converted during submission to Pathogenic.
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000201997 SCV000110277 pathogenic not provided 2013-07-25 criteria provided, single submitter clinical testing
GeneDx RCV000201997 SCV000149458 pathogenic not provided 2018-12-18 criteria provided, single submitter clinical testing This pathogenic variant is denoted MSH2 c.942+3A>T or IVS5+3A>T and consists of an A>T nucleotide substitution at the +3 position of intron 5 of the MSH2 gene. This variant has been reported in numerous individuals with personal and family histories consistent with Lynch syndrome (Liu 1994, Froggatt 1999, Kurzawski 2005, Buchanan 2014, Rosty 2014, Harper 2016, Roth 2016, Ziada-Bouchaar 2016). MSH2 c.942+3A>T was originally reported to be a pathogenic founder variant in Newfoundland, but has since been hypothesized to be a mutational hotspot with this variant being identified in individuals of varying ethnicities without a common haplotype identified, and was confirmed de novo in an individual diagnosed with colon cancer showing absence of MSH2 and MSH6 proteins via immunohistochemistry and endometrial cancer (Desai 2000, Win 2011). Additionally, Auclair et al. (2006) performed mRNA analysis and found that this variant led to skipping of exon 5. MSH2 c.942+3A>T has also been reported to be overrepresented in individuals with the Muir-Torre variant, suggesting a possible association with an increased risk for sebaceous neoplasms (South 2008, Roberts 2014). MSH2 c.942+3A>T was not observed in large population cohorts (Lek 2016). Based on the currently available evidence, we consider this variant to be pathogenic.
Ambry Genetics RCV000115549 SCV000185219 pathogenic Hereditary cancer-predisposing syndrome 2019-03-05 criteria provided, single submitter clinical testing Other strong data supporting pathogenic classification;Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation;Rarity in general population databases (dbsnp, esp, 1000 genomes);Functionally-validated splicing mutation
Invitae RCV000524424 SCV000211911 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-01-08 criteria provided, single submitter clinical testing This sequence change falls in intron 5 of the MSH2 gene. It does not directly change the encoded amino acid sequence of the MSH2 protein, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (rs193922376, ExAC no frequency). This variant has been reported to segregate with disease in many Lynch syndrome families worldwide (PMID: 8062247, 15222003, 19419416, 21681552, 22883484, 20682701, 10978353, 24310308). It is recognized as a causative allele for Lynch syndrome by the American College of Medical Genetics (PMID: 24310308). ClinVar contains an entry for this variant (Variation ID: 36580). Functional studies demonstrate that this variant disrupts mRNA splicing and results in skipping of exon 5 (PMID: 16395668, 8062247). For these reasons, this variant has been classified as Pathogenic.
Counsyl RCV000001844 SCV000487770 pathogenic Lynch syndrome I 2015-11-17 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000030256 SCV000592480 pathogenic Lynch syndrome 2017-01-03 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000201997 SCV000601495 pathogenic not provided 2019-05-17 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Statistically enriched in patients compared to ethnically matched controls. Found in at least one symptomatic patient. Nucleotide conservation is uninformative. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Color RCV000115549 SCV000690146 pathogenic Hereditary cancer-predisposing syndrome 2020-02-18 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000030256 SCV000711430 pathogenic Lynch syndrome 2016-03-18 criteria provided, single submitter clinical testing The c.942+3A>T variant in MSH2 has been reported in >150 individuals with Lynch syndrome and is considered a founder variant in the Newfoundland population (Lab Corp database, Woods 2010). Data from large population studies is insufficient t o assess the frequency of this variant. In vitro functional studies provide some evidence that the c.942+3A>T variant impacts splicing (Auclair 2006). In additi on, it has been classified as Pathogenic on December 18, 2013 by the ClinGen-app roved InSiGHT expert panel (ClinVar SCV000107794.2). In summary, this variant me ets our criteria to be classified as pathogenic for Lynch syndrome in an autosom al dominant manner based upon the on the predicted impact to the protein.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000001844 SCV000743207 pathogenic Lynch syndrome I 2017-07-28 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000001844 SCV000744270 pathogenic Lynch syndrome I 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000201997 SCV000806051 pathogenic not provided 2017-06-27 criteria provided, single submitter clinical testing
A.C.Camargo Cancer Center / LGBM, A.C.Camargo Cancer Center RCV000030256 SCV000914299 pathogenic Lynch syndrome 2019-01-30 criteria provided, single submitter research
Institute of Human Genetics, University of Leipzig Medical Center RCV000001844 SCV001428898 pathogenic Lynch syndrome I 2018-04-12 criteria provided, single submitter clinical testing
OMIM RCV000001844 SCV000021989 pathogenic Lynch syndrome I 2000-09-01 no assertion criteria provided literature only
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000201997 SCV000257198 pathogenic not provided no assertion criteria provided clinical testing
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001249912 SCV001423929 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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