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Clinical features

  • Familial adenomatous polyposis (FAP) predisposes to the development of adenomatous polyposis, with colonic polyp burden in the classic form of FAP in the order of 100s to 1000s, starting from the late teens.
  • There is an associated colorectal cancer risk in the order of 100% if risk-reducing interventions are not undertaken.
  • The severity of the disease phenotype varies depending on the underlying genotype. Genotype alone should not be used to guide management, however.
  • A significant proportion of patients with FAP also demonstrate polyps in the stomach or duodenum, with an associated increased risk of cancer. Certain pathogenic variants in the APC gene (in the YY1 binding domain of the 1B promoter) are associated with a phenotype that is almost completely limited to the stomach, known as gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS).
  • FAP also increases the risk of non-gastrointestinal tumours, including differentiated thyroid cancer (including cribriform morular variant of papillary thyroid cancer), childhood hepatoblastoma, brain tumours, adrenal adenomas and desmoid fibromatosis (characteristically CTNNB1-wild type).
  • Other non-neoplastic features have also been reported in FAP, including congenital hypertrophy of the retinal pigment epithelium (CHRPE), sebaceous cysts, dental anomalies and osteomas.


Genotype-phenotype correlations

Genotype alone should not be used to guide management of individuals found to carry pathogenic/likely pathogenic variants in APC, but certain genotype-phenotype correlations have been observed.

  • Some patients demonstrate an attenuated phenotype (attenuated (a)FAP), with lower polyp burden and later onset of disease. Certain genotypes are more likely to be associated with aFAP – including variants 5’ of codon 233, which lead to production of a truncated APC protein that is unable to dimerise with (and therefore interfere with) wild-type APC, as well as variants in a region of exon 9 in which alternative splicing events occur naturally. Variants in the extreme 3’ end of APC are associated with aFAP as well as with increased predisposition to desmoid tumours.
  • Other variants are associated with extremely severe phenotypes, including those between codons 1250 and 1464.
  • Variants in codons 1395-1493 appear to confer higher risks of desmoid tumours and osteomas compared to variants in certain other regions of APC.
  • Pathogenic variants in the YY1 binding domain of the 1B promoter of APC are associated with gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS).
  • A founder variant in APC has been identified in individuals of Ashkenazi Jewish ancestry that does not cause a characteristic FAP phenotype but appears to be a low-moderate colorectal cancer risk allele. The variant in question is APC: c.3920T>A p.(Ile1307Lys), (I1307K).
    • The polyp burden (if any) in carriers of this variant is typically fewer than 10 polyps.
    • The I1307K variant is found in up to 10% of individuals of Ashkenazi Jewish ancestry. In carriers of this ethnicity, this variant appears to confer a 1.5- to 2-fold risk of developing colorectal cancer compared to the general population. This risk does not appear to extend to carriers that do not have a reported Ashkenazi Jewish heritage, however, suggesting that there may be other linked/co-inherited genetic factors that contribute to the risk associated with this allele in certain populations.
    • At present, there is ongoing debate about how carriers of the APC I1307K variant should be managed, and whether cascade testing in at risk family members is needed. At present, management should be guided by personal and family history of polyposis/colorectal cancer, bearing in mind patient ethnicity and age.
    • Formal guidelines for management of carriers of APC I1307K are expected to be developed by The International Society for Gastrointestinal Hereditary Tumours (InSiGHT) in the near future.

Inheritance and genomic counselling

  • FAP is an autosomal dominant condition, such that each child and each sibling of an individual with an inherited APC variant has a 50% (1-in-2) chance of inheriting the condition.
  • It is the most common hereditary form of polyposis, but is still rare in the general population, occurring at a frequency of 1/6,850 to 1/31,250.
  • As colonoscopic screening is recommended starting from early teens, and hepatoblastoma screening may be considered in early childhood, predictive genomic testing in children may be appropriate after appropriate counselling.
  • A significant proportion (20%–25%) of constitutional (germline) APC variants arise ‘de novo’, such that family history may not be informative, and constitutional mosaicism is not infrequent.


  • Constitutional APC testing may be offered to a patient with colorectal cancer and/or adenomatous polyposis as part of a multigene panel for polyposis predisposition (R211: Inherited polyposis and early onset colorectal cancer – germline test) in the following scenarios:
    • colorectal cancer at under 40 years;
    • colorectal cancer and five or more adenomatous polyps;
    • five or more adenomatous polyps at under 40 years, 10 or more adenomatous polyps at under 60 years or 20 or more adenomatous polyps at any age; or
    • five or more adenomatous polyps at under 60 years) and first-degree relative with five or more adenomatous polyps (at under 60 years)
  • Constitutional (germline) APC testing will also be included as part of multigene panel testing for polyposis predisposition (R211: Inherited polyposis and early onset colorectal cancer – germline test) in individuals fulfilling criteria for serrated polyposis, or in individuals in whom hamartomatous polyposis is suspected, but an underlying constitutional variant in APC is much less likely to explain such phenotypes.
  • Single gene APC testing (R414: APC-associated polyposis) is offered to individuals with FAP-associated phenotypic features that may not yet have developed a colonic phenotype, including people with:
    • Multifocal or bilateral CHRPE as assessed by experienced ophthalmologist;
    • aggressive fibromatosis/desmoid tumour (somatic pathogenic variants in CTNNB1 should be excluded in the first instance);
    • cribriform-morular variant of papillary thyroid cancer;
    • hepatoblastoma; or
    • multiple osteomas of skull and mandible or multiple dental abnormalities (unerupted teeth, supernumerary teeth with dentigerous cysts or odontomas) in children/young adults.

Management and implications of genomic testing


  • As polyps may be evident from early adolescence, regular colonoscopy-based surveillance is recommended from the age 12–14, every one to three years depending on polyp burden.
  • Prophylactic panproctocolectomy with ileal pouch-anal anastomosis, or prophylactic total colectomy with ileorectal anastomosis is recommended when polyp burden is no longer manageable conservatively.
  • The role of chemoprevention in patients with FAP is uncertain, but research is ongoing to examine the role of sulindac and other related agents.
  • Regular oesophagogastroduodenoscopy from the early 20s is recommended to manage gastric/duodenal polyposis, with frequency based on polyp burden and Spigelman classification.
  • Annual clinical thyroid examination is recommended from the early 20s but the role of thyroid cancer screening in this setting is uncertain and not currently recommended outside of research studies.
  • Surveillance for hepatoblastoma in FAP is uncertain, but risk is highest before five years of age, dropping thereafter.
  • Referral of affected patients to clinical genetics should be arranged to discuss onward management, family planning implications, and cascade testing of relatives at risk.
  • Surveillance is best coordinated through an expert centre.

Family planning implications

The Human Fertilisation and Embryology Authority have approved the use of pre-implantation genomic testing for monogenic disorders (PGT-M) (previously known as pre-implantation genetic diagnosis, or PGD) for couples where one of the intended parents is a carrier of a likely pathogenic/pathogenic variant in APC. It is best practice that discussions regarding PGT-M and other family planning options be undertaken by a specialist genetic counsellor or clinical geneticist.

Other options may include prenatal testing (invasive, or non-invasive if the intended father is the carrier) with termination of affected embryos, adoption, gamete donation, or natural conception and pregnancy with testing of children in adulthood.


For clinicians


For patients

Tagged: Colorectal cancer, Constitutional mutations

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  • Last reviewed: 09/05/2022
  • Next review due: 09/05/2024
  • Authors: Dr Terri McVeigh