ClinVar Miner

Submissions for variant NM_000251.2(MSH2):c.645+1G>T (rs267607689)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
International Society for Gastrointestinal Hereditary Tumours (InSiGHT) RCV000076660 SCV000107695 likely pathogenic Lynch syndrome 2019-06-21 reviewed by expert panel curation Interrupts canonical donor splice site
Ambry Genetics RCV000220374 SCV000278343 pathogenic Hereditary cancer-predisposing syndrome 2018-05-15 criteria provided, single submitter clinical testing The c.645+1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide after coding exon 3 of the MSH2 gene. This alteration has been identified in a Polish suspected-Lynch syndrome family (Kurzawski G et al, Clin. Genet. 2006 Jan; 69(1):40-7). In addition, another alteration at the same position has been identified in high-risk families and associated with aberrant splicing in vitro (Gille JJ et al. Br J Cancer. 2002 Oct 7;87(8):892-7, Thompson BA et al. Hum Mutat. 2013 Jan;34(1):200-9). This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, the c.645+1G>T alteration is predicted to abolish the native splice donor 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. As such, this alteration is classified as a pathogenic mutation.

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