Familial Adenomatous Polyposis

About this condition

Familial adenomatous polyposis (FAP) is an autosomal dominant hereditary colorectal cancer syndrome caused by pathogenic variants in the APC (adenomatous polyposis coli) tumor suppressor gene on chromosome 5q22.2. Classic FAP is characterized by the development of hundreds to thousands of adenomatous polyps throughout the colorectum, typically appearing in the second decade of life. Without surgical intervention, colorectal cancer is virtually inevitable by the fifth decade — lifetime colorectal cancer risk approaches 100% in untreated classic FAP. FAP accounts for approximately 0.5-1% of all colorectal cancers and is estimated to affect 1 in 5,000 to 1 in 10,000 individuals.

Attenuated FAP (AFAP) is a milder phenotypic variant caused by variants in specific APC regions (the 5' end, exon 9, or the 3' end) and is characterized by fewer polyps (10-100), later onset of polyposis, lower but still substantially elevated colorectal cancer risk, and more variable expression. Genotype-phenotype correlations in FAP are well-established: variants in codons 1250-1464 (particularly codon 1309) are associated with dense polyposis and earlier colorectal cancer; variants at codons 1310-1330 and 1445-1580 are associated with a higher risk of desmoid tumors; and variants at the 5' end are associated with AFAP. Extracolonic manifestations — including duodenal adenomas (100% lifetime risk), thyroid cancer, hepatoblastoma (in children), desmoid tumors, congenital hypertrophy of the retinal pigment epithelium (CHRPE), and osteomas — vary by APC variant location.

Approximately 20-30% of classic FAP arises from de novo APC variants without a family history of polyposis. An additional 7-10% of patients who meet clinical criteria for FAP have no detectable APC variant by standard sequencing — this group may harbor deep intronic splicing variants, large genomic rearrangements (deletions, duplications), or somatic mosaicism that standard gene panel testing cannot detect. MUTYH-associated polyposis (MAP), caused by biallelic MUTYH variants, can produce a phenotype indistinguishable from attenuated FAP and requires concurrent MUTYH genotyping in APC-negative polyposis patients.

Classic FAP, attenuated FAP (AFAP), and MUTYH-associated polyposis (MAP) produce overlapping clinical pictures with distinct genetic causes and surgical implications. APC variant location determines extracolonic manifestation risk.

Gene locus: APC (5q22.2)

Standard hereditary cancer panels read APC coding exons. They miss deep intronic variants, large rearrangements, and mosaic mutations — the variants that explain negative panels in clinically affected families.

Up to 30% of clinically diagnosed FAP patients test APC-negative on standard panels

Standard hereditary cancer panels sequence the APC coding region and splice sites. They do not reliably detect large genomic deletions or duplications spanning multiple exons, deep intronic variants that create aberrant splice sites, or somatic mosaicism — where the APC variant is present in only a fraction of cells. Studies have found that 7-10% of classic FAP patients with no identified APC coding variant carry deep intronic or structural rearrangement variants detectable only by comprehensive genomic analysis. An additional subset harbor somatic mosaic APC mutations, where variant allele fractions of 10-20% may be missed by standard panel sequencing depths. Whole genome sequencing at 30X coverage with copy number variant analysis resolves all of these.

APC variant location determines surgical strategy and surveillance intensity

Colorectal surgical management in FAP is not one-size-fits-all. Patients with codons 1250-1464 variants and dense polyposis typically require restorative proctocolectomy with ileal pouch-anal anastomosis. Patients with AFAP or sparse polyposis may be managed with segmental colectomy with ileorectal anastomosis and endoscopic surveillance. Desmoid risk stratification — critical for surgical planning in patients with intra-abdominal desmoid tumor risk — depends on APC variant location at codons 1310-1580. None of these genotype-phenotype stratifications are possible without a complete APC genotype, which requires sequencing the full gene including regulatory and intronic regions.

Familial Adenomatous Polyposis — hundreds to thousands of colorectal polyps driven by APC loss-of-function, with near-certain cancer transformation without surgical intervention.