ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.226C>T (p.Gln76Ter) (rs63750042)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076447 SCV000107476 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation introducing premature termination codon
Invitae RCV000684780 SCV000548220 pathogenic Hereditary nonpolyposis colorectal neoplasms 2019-07-15 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln76*) in the MSH2 gene. It is expected to result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). ClinVar contains an entry for this variant (Variation ID: 90945). This particular truncation has been reported to segregate in affected family members of large Lynch syndrome families (PMID: 19669601), and in individuals with Lynch syndrome (PMID: 16034045, 20587412, 28874130, 22480969). This variant was also reported as homozygous in two siblings with mediastinal T-cell non-Hodgkin lymphoma at 2.5 years of age and hypopigmented skin lesions, consistent with CMMRD (PMID: 17601929). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
GeneDx RCV000202307 SCV000568620 pathogenic not provided 2018-10-12 criteria provided, single submitter clinical testing This variant is denoted MSH2 c.226C>T at the cDNA level and p.Gln76Ter (Q76X) 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 several individuals meeting Amsterdam II Criteria or Bethesda Guidelines for Lynch syndrome (Stormorken 2005, Sjursen 2010, Bonnet 2012). MSH2 Gln76Ter was also observed in multiple members of a large Kuwaiti family meeting Amsterdam Criteria; three members of this family presented in childhood with lymphoma and café-au-lait macules, and two of these children were confirmed to be homozygous for this variant (Scott 2007, Marafie 2009). Results from several functional assays in cells homozygous for MSH2 Gln76Ter were consistent with observations from MSH2 knockout mice, which have demonstrated reduced RAD51 loci and increased chromosome damage after ionizing radiation (Barwell 2007). This variant is considered pathogenic.
Ambry Genetics RCV000491576 SCV000580495 pathogenic Hereditary cancer-predisposing syndrome 2018-11-09 criteria provided, single submitter clinical testing Alterations resulting in premature truncation (e.g.reading frame shift, nonsense)
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000202307 SCV000257172 pathogenic not provided no assertion criteria provided research
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001250039 SCV001423964 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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