ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.388_389del (p.Gln130fs) (rs63750704)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076592 SCV000107625 pathogenic Lynch syndrome 2013-09-05 reviewed by expert panel research Coding sequence variation resulting in a stop codon
Ambry Genetics RCV000163755 SCV000214332 pathogenic Hereditary cancer-predisposing syndrome 2018-05-16 criteria provided, single submitter clinical testing Other acmg-defined mutation (i.e. initiation codon or gross deletion);Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
GeneDx RCV000235890 SCV000293505 pathogenic not provided 2015-11-12 criteria provided, single submitter clinical testing This deletion of 2 nucleotides in MSH2 is denoted c.388_389delCA at the cDNA level and p.Gln130ValfsX2 (Q130VfsX2) at the protein level. The normal sequence, with the bases that are deleted in braces, is CTCT[CA]GTTT. The deletion causes a frameshift, which changes a Glutamine to a Valine at codon 130, and creates a premature stop codon at position 2 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. MSH2 c.388_389delCA has been observed in association with Lynch syndrome related cancer and is considered a founder mutation in individuals of Portuguese ancestry (Mangold 2005, Dominguez-Valentin 2013, Pinheiro 2013). We consider this variant to be pathogenic.
Color RCV000163755 SCV000690106 pathogenic Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000076592 SCV000917697 pathogenic Lynch syndrome 2018-05-10 criteria provided, single submitter clinical testing Variant summary: MSH2 c.388_389delCA (p.Gln130ValfsX2) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. Truncations downstream of this position have been classified as pathogenic by our laboratory (eg. c.528_529delTG, p.Cys176X; c.704_705delAA, p.Lys235fsX20). The variant was absent in 121404 control chromosomes. c.388_389delCA has been reported in the literature in multiple individuals affected with Lynch Syndrome. The variant was reported as a founder mutation in Portuguese Lynch syndrome families (Pinheiro_2013). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Invitae RCV000816977 SCV000957509 pathogenic Hereditary nonpolyposis colon cancer 2019-12-17 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Gln130Valfs*2) 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). This variant has been observed in many families affected with Lynch syndrome (PMID: 15849733, 23170986, 24344984), and has been reported to be a founder mutation in the Portuguese population (PMID: 23170986). ClinVar contains an entry for this variant (Variation ID: 91090). Loss-of-function variants in MSH2 are known to be pathogenic (PMID: 15849733, 24362816). For these reasons, this variant has been classified as Pathogenic.
OMIM RCV000087058 SCV000119872 pathogenic Lynch syndrome I 2013-09-01 no assertion criteria provided literature only

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