Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075258 | SCV000106256 | pathogenic | Lynch syndrome | 2013-09-05 | reviewed by expert panel | research | Multifactorial likelihood analysis posterior probability >0.99 |
| Ambry Genetics | RCV002399435 | SCV002704934 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-03-18 | criteria provided, single submitter | clinical testing | The c.1559-2A>T intronic pathogenic mutation results from an A to T substitution two nucleotides upstream from coding exon 14 in the MLH1 gene. This mutation (designated as IVS13-2A>T) was reported in a patient diagnosed with MSI-H, MLH1/PMS2-absent colorectal cancer at age 34 whose family history met Amsterdam criteria (Southey MC et al. J. Clin. Oncol. 2005 Sep;23:6524-32; Jenkins MA et al. Clin. Gastroenterol. Hepatol. 2006 Apr;4:489-98). It was also observed in a 43-year-old patient with colorectal cancer that showed reduced MLH1 staining and complete loss of PMS2 staining on IHC (Walsh MD et al. Mod. Pathol. 2012 May;25:722-30). This alteration also demonstrated out-of-frame exon 14 as well as exon 14/15 skipping in a splicing assay using patient RNA for RT-PCR analysis (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). This alteration has been classified as pathogenic using the following lines of evidence: in silico prediction models, segregation with disease, clinical phenotype including tumor characteristics, mutation co-occurrence, and functional studies (Thompson BA et al. Hum. Mutat. 2013 Jan;34:200-9; Thompson BA et al. Nat. Genet. 2014 Feb;46:107-15; available at [www.insight-group.org/variants/classifications/]). 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. In addition to the clinical data presented in the literature, 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. |