The packet lists APC (chromosome 5) as the associated gene, with autosomal dominant inheritance. GeneReviews describes APC as consisting of 15 exons and 2843 codons, with most germline variants in the 5' half of the gene. It reports that germline variants in the central part of the gene are often associated with classic FAP, variants between codons 1250 and 1464 with profuse polyposis, and variants at the 5' or 3' ends with attenuated FAP, while noting that genotype does not always predict colorectal phenotype and that wide phenotypic variability occurs with the same variant. Whole-gene deletion is listed with the classic form. GeneReviews states that penetrance is 100% in FAP, that penetrance of colonic polyposis in attenuated FAP is less well understood, and that penetrance in GAPPS is unknown.

Per GeneReviews, the majority of individuals have an affected parent, and up to 25% of individuals with FAP have the disorder as a result of a de novo pathogenic variant. If a parent is affected or known to carry the APC pathogenic variant, the risk to siblings of inheriting it is 50%.

GeneReviews describes NCCN-based features prompting suspicion of an APC-associated polyposis condition: multiple colorectal adenomatous polyps (at least 10-20 cumulative), a family history of multiple polyps or a known APC pathogenic variant, hepatoblastoma, multifocal or bilateral congenital hypertrophy of the retinal pigment epithelium, desmoid tumor, and the cribriform-morular variant of papillary thyroid cancer.

According to GeneReviews, the diagnosis is established by identification of a heterozygous germline pathogenic or likely pathogenic variant in APC; a variant of uncertain significance neither establishes nor rules out the diagnosis. Classic FAP is considered with such a variant plus at least 100 colorectal adenomatous polyps (or multiple polyps and a relative with confirmed classic FAP), and attenuated FAP with such a variant plus a relative with confirmed attenuated FAP and/or fewer polyps. GeneReviews' differential diagnosis lists other hereditary polyposis and colorectal cancer syndromes, including Lynch syndrome and juvenile polyposis syndrome, which are distinguished by molecular genetic testing, histopathology, and phenotype.

The packet does not certify a foundational-therapy field or an approved-treatments record with market status for this condition. Its orphan-drug listing records nirogacestat (Ogsiveo; SpringWorks Therapeutics) with status APPROVED for desmoid tumor (aggressive fibromatosis), a recognized manifestation listed among the phenotypes; several other agents carry orphan designation for desmoid tumors, and designation does not indicate approval. The remainder of this section draws on the GeneReviews management section.

For colonic polyps, it describes endoscopic surveillance with colonoscopy beginning between ages 10 and 15 years at one- to two-year intervals, with polyp resection, and delay of colectomy when polyp burden is manageable. Indications for colectomy are described as including documented or suspected colorectal cancer, significant symptoms, or adenoma burden not manageable endoscopically. For attenuated FAP, colonoscopy may begin in late adolescence, and about one third of individuals have polyp numbers limited enough for periodic colonoscopic polypectomy. Surgical options described are total proctocolectomy with ileal pouch anal anastomosis (a multistage surgery), total colectomy with ileorectal anastomosis, and total proctocolectomy with permanent ileostomy; the choice depends on clinical circumstances and rectal polyp burden. GeneReviews states that desmoid risk is increased after abdominal surgery and may be higher after two-stage procedures, and that fecundity may be lower in women after total colectomy with ileal pouch anastomosis.

Surveillance beyond the colon is described as including upper endoscopy with visualization of the ampulla of Vater every 6 months to 5 years beginning at age 20-25 years, depending on duodenal adenoma burden; thyroid examination and ultrasound every 2-5 years from late adolescence; annual neurologic examination; and hepatoblastoma assessment every 3-6 months in the first five years of life.

The packet does not include a certified natural-history or survival field. GeneReviews states that without colectomy colorectal cancer is essentially inevitable in classic FAP, with untreated cumulative figures of 7% by age 21, 87% by 45, and 93% by 50, though asymptomatic individuals in their 50s have been reported. For attenuated FAP it estimates cumulative colorectal cancer risk of about 70% by age 80. It reports that 57% of individuals with FAP and ileal pouches in one study had adenomatous polyps in the pouch. Individual outcomes are not certified in this packet.

The packet lists numerous clinical trial records on ClinicalTrials.gov for this condition. Records that name familial adenomatous polyposis include NCT06557733, a Phase 2 study titled as an investigational drug (TPST-1495) (National Cancer Institute, recruiting); NCT05552755, a Phase 1 study titled as evaluating REC-4881 (Recursion Pharmaceuticals, recruiting); NCT05630794, a Phase 1 study titled as testing safety and colorectal cancer preventive effects of ONC201 (National Cancer Institute, recruiting); NCT06308445, a Phase 2 safety study of rapamycin in children (University Hospital, Toulouse, not yet recruiting); and NCT06641310, an exercise therapy trial (University of Michigan Rogel Cancer Center, recruiting). GeneReviews' therapies-under-investigation section reports that in a single controlled trial eicosapentaenoic acid led to a 20%-30% decrease in polyp size and number, cites a Phase III trial of it after colectomy with ileorectal anastomosis (NCT03806426). A trial title does not by itself establish the intervention, and listing does not imply efficacy or approval.