ClinVar Miner

Submissions for variant NM_000251.3(MSH2):c.1277-2A>T

dbSNP: rs267607949
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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
University of Washington Department of Laboratory Medicine, University of Washington RCV000758598 SCV000887351 likely pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.1277-2A>T has a 98.1% probability of pathogenicity based on combining prior probability from public data with a likelihood ratio of 1.56 to 1, generated from evidence of seeing this as a somatic mutation in a tumor without loss of heterozygosity at the MSH2 locus. See Shirts et al 2018, PMID 29887214.
Ambry Genetics RCV002370011 SCV002686381 pathogenic Hereditary cancer-predisposing syndrome 2021-08-03 criteria provided, single submitter clinical testing The c.1277-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 8 in the MSH2 gene. Using a Bayesian analysis that incorporates tumor mutation data, this variant was classified as likely pathogenic (Shirts BH et al. Am J Hum Genet, 2018 07;103:19-29). Two alterations impacting the same acceptor site (c.1277-2A>G and c.1277-1G>A) have been detected in individuals meeting either Amsterdam criteria or Bethesda guidelines for hereditary non-polyposis colorectal cancer (HNPCC)/Lynch syndrome and had colorectal tumors displaying high microsatellite instability with loss of MSH2 protein staining on immunohistochemistry (Sheng JQ et al. Chin J Dig Dis, 2006;7:197-205; Goldberg Y et al. Fam. Cancer, 2008 Apr;7:309-17; Sjursen W et al. J. Med. Genet., 2010 Sep;47:579-85; Tian W et al. Int J Cancer. 2019 Sep 1;145(5):1290-1298). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. 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. As such, this alteration is classified as a disease-causing mutation.

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