Submission Details

APC variants have been reported for over 30 years in relation to autosomal dominant Familial Adenomatous Polyposis (FAP) (PMIDs: 1651174, 1651562, 1651563), with subsequent recognition of classical (cFAP) and attenuated (aFAP) phenotypes. The cFAP patients develop more than 100 adenomatous colon polyps, while aFAP is a less severe form of familial polyposis, which is characterized by a lower number of adenomatous polyps (fewer than 100). Individuals with aFAP are also likely to develop polyps and colorectal cancer later in life than cFAP patients. cFAP is usually caused by germline mutations in the APC gene between codons 178 and 1580. However, germline mutations associated with aFAP tend to cluster in specific regions of the APC gene the 5′ end (codons 1–177, exons 1–4); the 3′ end (distal to codon 1580); and the alternatively spliced region of exon 9 (codons 311–408). Colonic polyp number varied greatly among aFAP patients and 5′ mutants generally had more polyps than other aFAP patients (PMID: 16461775). Although there are some differences between cFAP and aFAP, we found no difference in inheritance pattern and similarities in phenotypes and molecular mechanisms (both caused by loss of function alleles), per criteria outlined by the ClinGen Lumping and Splitting Working Group. Therefore, cFAP and aFAP have been lumped into one disease entity, classic or attenuated familial adenomatous polyposis (MONDO:0021057) in this curation. Note that APC variants have been also associated with Gastric Adenocarcinoma and Proximal Polyposis of the Stomach Syndrome (GAPPS) and were curated separately. 3 frameshift variants between codons 178 and 1580 identified from 6 cFAP patients (PMID: 8162051) and 2 frameshift variants (PMIDs:8625067 and 9824584 at 5’ and 3’ ends respectively) identified from 9 aFAP patients were included in this curation. More evidence is available in the literature, but the maximum score for genetic evidence (12 points) has been reached. This gene-disease association is also supported by experimental evidence (6 points) including two mouse models showing intestinal polyps and tumor formation for mice bearing APC truncations (PMIDs: 7753829 and 8090754) as well as functional alteration assays in patient colon cells displaying differential localization of beta-catenin in cells with mutations in APC compared to wild type (PMID: 8521819). In addition, experiments in non-patient cells show APC truncating variants affect cell cycle progression in mouse NIH 3T3 cells, and failure of truncated APC to inhibit growth of monkey kidney fibroblast CV-11 cells (PMID: 8521819). In summary, heterozygous APC truncating mutations are definitively associated (18 points) with classic or attenuated familial adenomatous polyposis (MONDO:0021057). This has been repeatedly demonstrated in both the research and clinical diagnostic settings, and has been upheld over time.