Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Laboratory for Molecular Medicine, |
RCV000606942 | SCV000731722 | likely pathogenic | Familial multiple polyposis syndrome | 2017-11-02 | criteria provided, single submitter | clinical testing | The c.1409-2A>G variant in APC has been reported in 1 individual with familial a denomatous polyposis (FAP, LMM unpublished data), in at least 1 individual with attenuated FAP (Aretz 2004, Friedl 2005), and was absent from large population s tudies. This variant occurs in the invariant region (+/- 1,2) of the splice cons ensus sequence and has been observed to cause skipping of exon 11 of APC (Aretz 2004), resulting in a truncated protein that is lacking 32 amino acids. Other va riants at this splice site have been reported in the Human Gene Mutation Databas e (HGMD) in association with FAP, one affecting the same nucleotide and two affe cting the -1 position (Stenson 2017). In summary, while additional studies are r equired to fully establish its clinical significance, the c.1409-2A>G variant is likely pathogenic. ACMG/AMP criteria applied: PM2, PM4, PP3, PS4_Supporting (Ri chards 2015). |
| Ambry Genetics | RCV002395627 | SCV002702516 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-11-01 | criteria provided, single submitter | clinical testing | The c.1409-2A>G intronic pathogenic variant results from an A to G substitution two nucleotides upstream from coding exon 11 in the APC gene. This alteration has been identified in patient cohorts with clinical diagnoses of FAP or AFAP (Friedl W et al. Hered Cancer Clin Pract, 2005 Sep;3:95-114; Aretz S et al. Hum Mutat, 2004 Nov;24:370-80). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. 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. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003478330 | SCV004220501 | pathogenic | not provided | 2022-12-21 | criteria provided, single submitter | clinical testing | This variant disrupts a canonical splice-acceptor site and interferes with normal APC mRNA splicing. This variant has not been reported in large, multi-ethnic general populations (http://gnomad.broadinstitute.org). In the published literature, the variant has been reported in individuals/families with familial adenomatous polyposis (FAP) (PMID: 15459959 (2004) and 20223039 (2005)). Based on the available information, this variant is classified as pathogenic. |