ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.1077-1G>T (rs267607944)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076020 SCV000107041 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
University of Washington Department of Laboratory Medicine, University of Washington RCV000076020 SCV000887350 pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.1077-1G>T has a 99.96% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 26.5 to 1, generated from evidence of seeing this as a somatic mutation in a tumor with loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics RCV001009855 SCV001169976 pathogenic Hereditary cancer-predisposing syndrome 2018-11-09 criteria provided, single submitter clinical testing The c.1077-1G>T intronic variant results from a G to T substitution one nucleotide upstream from coding exon 7 of the MSH2 gene. Based on cDNA studies, this alteration is predicted to cause in-frame exon 7 skipping as a major product and is predicted create an ectopic acceptor which causes an out-of-frame insertion of 83 nucleotides as a minor product (at least 10%). Two tumors were analyzed in this study and demonstrated high microsatellite instability and absent MSH2 protein expression (Arnold S et al. Hum. Mutat., 2009 May;30:757-70). A different nucleotide substitution at that same position (c.1077-1G>C) is also classified as a disease-causing mutation internally. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

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