Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| International Society for Gastrointestinal Hereditary Tumours |
RCV000075720 | SCV000106731 | likely pathogenic | Lynch syndrome | 2019-06-21 | reviewed by expert panel | curation | Interrupts canonical donor splice site |
| Ambry Genetics | RCV002336223 | SCV002637212 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-02-17 | criteria provided, single submitter | clinical testing | The c.454-1G>T intronic pathogenic mutation results from a G to T substitution one nucleotide upstream from coding exon 6 of the MLH1 gene. This mutation was detected in a patient with colorectal cancer at age 42 (Aaltonen LA et al. N Engl J Med, 1998 May;338:1481-7). Two other alterations impacting the same acceptor site (c.454-1G>C and c.454-1G>A) have been described in numerous HNPCC/Lynch syndrome families, including patients whose tumors demonstrated MSI and loss of MLH1 protein (Nyström-Lahti M et al. Hum. Mol. Genet. 1996;5(6):763-9; Lagerstedt Robinson K et al. J. Natl. Cancer Inst. 2007;99(4):291-9; Lotsari JE et al. Breast Cancer Res. 2012;14(3):R90). This variant was not reported in population-based 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. |