ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.2634+1G>T (rs267608019)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076519 SCV000107549 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 RCV000076519 SCV000887429 pathogenic Lynch syndrome 2018-05-01 criteria provided, single submitter clinical testing MSH2 NM_000251.2:c.2634+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 RCV001016179 SCV001177101 pathogenic Hereditary cancer-predisposing syndrome 2019-07-24 criteria provided, single submitter clinical testing The c.2634+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 15 of the MSH2 gene. 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 donor site; however, direct evidence is unavailable. This alteration has been identified in multiple colorectal cancer/Lynch syndrome cohorts (Yuen ST et al. Oncogene 2002 Oct;21:7585-92; Mangold E et al. Int. J. Cancer 2005 Sep;116:692-702; Sjursen W et al. J. Med. Genet. 2010 Sep;47:579-85; Bonadona V et al. JAMA 2011 Jun;305(22):2304-10). Bayesian analysis using a likelihood ratio derived from tumor data assigned this variant a 99.96% posterior probability of pathogenicity (Shirts BH et al. Am. J. Hum. Genet., 2018 07;103:19-29). In addition to the published data, 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.
Invitae RCV001386003 SCV001586074 pathogenic Hereditary nonpolyposis colorectal neoplasms 2020-07-27 criteria provided, single submitter clinical testing This sequence change affects a donor splice site in the last intron (intron 15) of the MSH2 gene. While this is not anticipated to result in nonsense mediated decay, it likely alters RNA splicing and results in a disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Lynch syndrome (PMID: 12386821, 21642682, 15849733). It has also been observed to segregate with disease in related individuals. This variant is also known as IVS15+IG>T in the literature. ClinVar contains an entry for this variant (Variation ID: 91017). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site, but this prediction has not been confirmed by published transcriptional studies. For these reasons, this variant has been classified as Pathogenic.
Constitutional Genetics Lab,Leon Berard Cancer Center RCV001250026 SCV001423951 pathogenic Lynch-like syndrome 2019-07-01 no assertion criteria provided clinical testing

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