FAP1 is caused by pathogenic variants in the APC gene on chromosome 5. The condition is inherited in an autosomal dominant pattern, meaning one altered copy of the gene is sufficient to cause the condition; each child of an affected individual has a 50% chance of inheriting the pathogenic variant. Up to 25% of cases arise from de novo pathogenic variants not inherited from either parent.

In classic FAP, penetrance is 100%: essentially all individuals carrying a pathogenic APC variant will develop colorectal adenomatous polyposis. In the attenuated form, the colorectal cancer risk by age 80 is estimated at approximately 70%, and the overall penetrance of colonic polyposis is less well established. Even among individuals who are affected, phenotypic expression varies substantially—a characteristic known as variable expressivity—with differences in polyp number, age of onset, and extracolonic manifestations observed even within the same family.

Variant location within APC generally correlates with clinical presentation. Variants in the central region are more commonly associated with classic FAP and profuse polyposis; variants at the 5′ or 3′ ends are more often associated with the attenuated form; and variants in codons 1395–1493 carry a higher risk of desmoid tumor development. These correlations are informative but do not reliably predict individual clinical outcomes, as variability within families is substantial.

Somatic mosaicism for APC pathogenic variants has also been documented, in which the genetic change occurs after fertilization and is present in only a subset of cells. Phenotypic severity in somatic mosaicism often reflects the proportion and tissue distribution of cells carrying the variant.

The diagnosis of an APC-associated polyposis condition is established by identification of a heterozygous germline pathogenic variant in APC through molecular genetic testing, which includes both sequencing and deletion/duplication analysis of the gene.

Features that raise clinical suspicion include multiple colorectal adenomatous polyps (generally at least 10–20 cumulative), a family history of adenomatous polyposis or a known APC pathogenic variant, hepatoblastoma, bilateral or multifocal CHRPE, desmoid tumor, or a cribriform-morular variant of papillary thyroid cancer. Additional suggestive features include dental abnormalities such as osteomas and supernumerary teeth, duodenal adenomas, and early-onset colorectal cancer with few polyps.

Classic FAP is characterized by 100 or more colorectal adenomatous polyps in the setting of a confirmed APC pathogenic variant. The attenuated form is characterized by fewer than 100 adenomas or adenoma onset at older ages, also with a confirmed APC pathogenic variant. Other hereditary polyposis and colorectal cancer syndromes—including MUTYH-associated polyposis, Lynch syndrome, and juvenile polyposis syndrome—are distinguished from APC-associated conditions through molecular genetic testing, histopathological assessment, and clinical features.

Management of FAP1 involves a multidisciplinary team and is tailored to disease subtype, polyp burden, age at presentation, and individual clinical circumstances.

For colonic disease, endoscopic surveillance with colonoscopy is a central component of management, generally beginning in the second decade of life for classic FAP and in late adolescence for attenuated FAP, at one- to two-year intervals. Colectomy becomes indicated when polyp burden cannot be adequately managed endoscopically, when adenomas with high-grade dysplasia are present, or when other clinical criteria are met. Surgical approaches include total proctocolectomy with ileal pouch anal anastomosis, total colectomy with ileorectal anastomosis, and total proctocolectomy with permanent ileostomy; the appropriate procedure depends on rectal polyp burden and individual clinical factors.

Long-term management includes regular surveillance for potential complications across multiple organ systems. Upper endoscopy for duodenal and gastric polyps typically begins between ages 20 and 25 or prior to colectomy. Thyroid evaluation is performed every two to five years starting in late adolescence. Annual neurologic examination and periodic abdominal surveillance during childhood are part of established monitoring protocols. Desmoid tumors, which may arise spontaneously or following abdominal surgery, require specialized oncologic evaluation; treatment options exist for desmoid tumor management. The association between staged abdominal surgery and increased desmoid risk has been documented, particularly for individuals with variants in codons 1395–1493 or a family history of desmoid tumors.

Several systemic agents are under active investigation for polyposis management and chemoprevention in FAP1. Patient assistance programs may be available to help cover treatment costs.

In classic FAP, colorectal cancer is essentially inevitable without surgical intervention, with onset typically occurring in the late third to fourth decade of life in untreated individuals; the cumulative risk approaches near-universal by the fifth decade. In attenuated FAP, the cumulative colorectal cancer risk is estimated at approximately 70% by age 80 without intervention, with cancer onset typically one to two decades later than in classic FAP.

Outcomes depend substantially on age at diagnosis, adherence to surveillance protocols, timing of colectomy, and management of extracolonic cancer risks. The lifetime cancer risk at extracolonic sites—including the small bowel (4–12% lifetime risk in the duodenum), thyroid, liver, and central nervous system—contributes to the long-term prognosis and requires ongoing monitoring. Identification of at-risk family members and adherence to established surveillance programs can substantially alter the natural history of the condition.

Numerous ongoing clinical trials are investigating new approaches for familial adenomatous polyposis 1, spanning chemoprevention strategies, polyposis management interventions, and related cancer risk reduction. Active clinical trials for this condition are listed on ClinicalTrials.gov. The published research landscape includes a substantial body of basic science and preclinical work, with active areas encompassing gene therapy approaches and biomarker investigation.