Total submissions: 1
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000568374 | SCV000675948 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | The c.1312+3A>C intronic pathogenic mutation results from an A to C substitution 3 nucleotides after coding exon 9 in the APC gene. This alteration has been detected in an individual diagnosed with >100 adenomatous polyps (Tsukanov AS et al. Russian J of Genet. 2017;53(3):369-375). Another alteration impacting the same donor site (c.1312+3A>G) has been detected in numerous familial adenomatous polyposis (FAP) families (Aretz S, et al. Hum. Mutat. 2004 Nov; 24(5):370-80; Lagarde A, et al. J. Med. Genet. 2010 Oct; 47(10):721-2; Nielsen M, et al. Clin. Genet. 2007 May; 71(5):427-33; Filipe B, et al. Clin. Genet. 2009 Sep; 76(3):242-55; Ambry internal data) and RNA analysis has shown that the c.1312+3A>G alteration leads to exon 9 skipping (Ambry internal data; Aretz S et al. Hum Mutat. 2004 Nov;24(5):370-80). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |