Gene test interpretation: APC

INTRODUCTION — This monograph summarizes the interpretation of germline testing of the APC gene. It does not discuss indications for testing and is not intended to replace clinical judgment in the decision to test or the care of the tested individual. These subjects are discussed separately [1].

OVERVIEW

How to read the report — An approach to reviewing a genetic test report is summarized in the checklist (table 1).

Testing involves two steps: determining the genotype and interpreting the pathogenicity of the variant(s).

●Genotype – Identifies variants. Should be repeated in a Clinical Laboratory Improvement Amendments (CLIA)-certified laboratory if the results were obtained by direct-to-consumer testing or a research study and would impact clinical care (eg, positive finding, negative finding in an individual with a suspected cancer syndrome).

●Interpretation – Determines pathogenicity of the variants identified. May require updating, especially for variants of unknown significance (VUS). (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Genetics'.)

The table provides a glossary of genetic testing terms (table 2).

Disease associations — Pathogenic and likely pathogenic variants in APC are associated with familial adenomatous polyposis (FAP), an autosomal dominant disorder. Individuals with FAP are at increased risk for developing gastrointestinal polyps and several cancers. The location of the variant within the APC gene can influence the severity of colonic polyposis, degree of cancer risk, age of cancer onset, and likelihood of extracolonic manifestations.

Variants associated with attenuated FAP (AFAP) are typically located at the far 5' or 3' ends of the APC gene.

A commonly reported APC variant, p.Ile1307Lys (p.I1307K; c.3920T>A), is found in approximately 8 percent of Ashkenazi Jewish individuals. This variant, often reported as a moderate or increased risk allele by laboratories, is not associated with colonic polyposis or FAP, but it increases the risk of colorectal cancer by 1.5- to twofold. Risks for other cancer types have not been established.

●Intestinal tumors

•Classic FAP is characterized by the presence of multiple colorectal adenomas. In classic FAP, there are >100 adenomatous colorectal polyps. Polyposis typically develops in the second or third decade of life. Colorectal cancer occurs in essentially all untreated individuals.

•AFAP is characterized by 10 to 100 adenomas. Individuals with AFAP have up to an 80 percent risk of developing colorectal cancer at an average age of 56 years.

•Duodenal adenomas occur in 45 to 90 percent of individuals with FAP, most commonly at or adjacent to the ampulla. Patients with FAP have a 5 percent lifetime risk of duodenal cancer.

•Gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) is characterized by >100 fundic gland polyps in the gastric body and fundus with antral sparing. Individuals with GAPPS have a high risk of gastric cancer. Colorectal polyposis generally does not occur.

●Extraintestinal manifestations – Individuals with FAP are at risk for follicular or papillary thyroid cancer, childhood hepatoblastoma, and central nervous system tumors, but these are much less common than colorectal and duodenal cancers.

Other extraintestinal manifestations of FAP include congenital hypertrophy of the retinal pigment epithelium, cutaneous lesions (epidermoid cysts, fibromas, lipomas, pilomatricomas), and osteomas and dental abnormalities. (See "Clinical manifestations and diagnosis of familial adenomatous polyposis", section on 'Extracolonic manifestations'.)

INDIVIDUALS WITHOUT CANCER

Implications of a pathogenic or likely pathogenic variant — We consider all individuals with a pathogenic or likely pathogenic variant in APC to be at risk for familial adenomatous polyposis (FAP), regardless of the initial reason for testing. Exceptions are noted above (see 'Disease associations' above). Information on the APC variant (eg, location within the gene) and personal and family history may help determine if the individual should be managed as having classic or attenuated FAP (AFAP).

Discussion should include the range of cancer risks, possible interventions for surveillance or risk reduction, and implications for family members. (See 'At-risk relatives' below.)

Counseling may require additional visits or referrals. Acting upon genetic test results is rarely an emergency; the individual can be reassured that management decisions can be deferred until questions are answered.

We adhere to National Comprehensive Cancer Network (NCCN) recommendations for surveillance and risk reduction [2]. Findings in family members (type of cancers, age of onset) may also inform surveillance (starting at an earlier age if a family member has an earlier age of onset).

In addition to annual physical examination, several evaluations and interventions are recommended to reduce the risk of FAP-associated cancers (algorithm 1).

●Colorectal cancer

•Increased screening/surveillance:

-Individuals with a pathogenic APC variant and/or clinical features of classic FAP should have annual colonoscopy starting around age 10 to 15 years. Patients should continue to undergo annual colonoscopy in the absence of an indication for colectomy.

-Individuals with a pathogenic variant in APC and clinical features of AFAP should have a colonoscopy every one to two years starting in the late teens. Patients with colorectal polyps should undergo polypectomy when feasible, followed by annual colonoscopy.

•Colectomy in patients with any of the following:

-Documented or suspected colorectal cancer

-Severe symptoms (eg, gastrointestinal bleeding)

-Adenomas with high-grade dysplasia or multiple adenomas >6 mm

-Marked increases in polyp number on consecutive examinations

-Inability to adequately survey the colon because of multiple diminutive polyps

•Endoscopic evaluation of the rectum and ileal pouch every six to 12 months depending on polyp burden (annually for end-ileostomies) following colectomy.

●Upper gastrointestinal tract

•Individuals with FAP should have screening for gastric and duodenal polyps, with upper endoscopy and duodenoscopy. This is initiated at the onset of colonic polyposis or age 20 to 25 years, whichever comes first. Screening should be performed earlier if there is a history of early onset gastroduodenal cancer in the family.

•Those without duodenal adenomas can have repeat upper endoscopy and duodenoscopy every four years (some expert groups suggest every five years).

•Those with duodenal adenomas should have complete polypectomy or sampling of duodenal polyps at the time of initial discovery and on each subsequent examination. An abnormal-appearing papilla should be biopsied. The frequency of upper endoscopies varies based on the severity of duodenal polyposis as classified by the Spigelman score (table 3):

-Stage 0: Every 3 to 5 years

-Stage I: Every 2 to 3 years

-Stage II: Every 1 to 2 years

-Stage III: Every 6 to 12 months

-Stage IV: Every 3 to 6 months (in the absence of duodenectomy)

●Desmoid tumors

•Abdominal computed tomography to assess for intra-abdominal desmoid tumors in the following individuals:

-Prior to colectomy if at increased risk for desmoids

-Palpable abdominal mass

-Symptoms suggestive of obstruction

●Thyroid cancer

•Individuals with classic or AFAP should have a thyroid ultrasound every two to five years, beginning in the late teens.

●Hepatoblastoma

•Screening for hepatoblastoma is controversial. If there is a family history of hepatoblastoma, we screen with serum alpha-fetoprotein, liver palpation, and abdominal ultrasound every three to six months from infancy until age five years.

●Other cancers

•Routine screening is not recommended for small bowel, pancreas, and central nervous system cancers. However, the decision should be individualized based on family history.

Additional details and supporting evidence are discussed separately. (See "Familial adenomatous polyposis: Screening and management of patients and families".)

Implications of a negative test — Negative testing means no pathogenic variants were identified (algorithm 1). However, some tests only evaluate a subset of variants; pathogenic variants might be present in other parts of the gene (if testing was not comprehensive) or in other genes.

●If the familial APC variant is known and the tested individual does not have that variant, usually they can be reassured that they are not at high risk for FAP-associated cancers, with caveats outlined above (see 'How to read the report' above). However, it is important provide an individualized risk assessment based on family history and other risk factors.

●If a familial APC variant is not known and results of genetic testing are negative, additional risk factors (genetic or acquired) may be present, and additional testing (for other APC variants or with a gene panel that includes other colorectal cancer genes) and/or surveillance is based on family history and other risk factors. Referral to a clinical geneticist, oncologist, or genetic counselor may be helpful to determine optimal testing in those with a strong family history of cancer. (See 'Locating a genetics expert' below.)

Implications of a VUS — Individuals with a variant of uncertain significance (VUS) should be managed based on their personal and family history and not the VUS (algorithm 1).

New information may become available; the testing laboratory or other resources should be consulted periodically for updates (eg, annually).

PATIENTS WITH COLORECTAL CANCER — The implications of genetic test results should be discussed with the individual's oncologist or surgeon; in some cases, referral to a specialist in hereditary colorectal cancer syndromes may be appropriate.

The presence of a pathogenic or likely pathogenic APC variant may impact several aspects of management; examples include:

●More extensive colectomy (eg, total colectomy with ileorectal anastomosis or proctocolectomy to reduce the risk of metachronous cancers based on patient age and rectal polyp burden.

●Additional screening and prophylactic measures. (See 'Implications of a pathogenic or likely pathogenic variant' above.)

Counseling and testing of family members are also often appropriate. (See 'Considerations for family members' below.)

For individuals with a negative test or a variant of uncertain significance (VUS) who have reasons to be concerned about a genetic cause, additional genetic testing may be appropriate. The need for additional testing may be discussed with a genetic counselor, the primary oncologist, or other hereditary colorectal cancer specialists. (See 'Locating a genetics expert' below.)

CONSIDERATIONS FOR FAMILY MEMBERS

Preconception counseling — Preconception counseling is appropriate for individuals with a pathogenic or likely pathogenic APC variant who are considering childbearing.

Some may elect to conceive using donor gametes or in vitro fertilization (IVF) with preimplantation genetic testing (PGT). (See "Preimplantation genetic testing", section on 'Patients known to be at increased risk of offspring with a specific medically actionable condition'.)

At-risk relatives — Individuals with a pathogenic variant or likely pathogenic APC variant should inform their at-risk relatives about the importance of genetic counseling and possible testing.

●The risk of having inherited the variant is 50 percent for first-degree relatives. Others at-risk may include aunts, uncles, nieces, nephews, and cousins.

●Usually, the variant segregates on the side of the family with a history of cancer; however, if possible, it is recommended to test a parent or other relative with cancer.

●Genetic testing for at-risk relatives may be considered as early as 10 to 12 years for classic familial adenomatous polyposis (FAP) and the late teens for attenuated FAP (AFAP). Age of polyposis onset for relatives may help guide the timing.

●Families facing decisions to test minors should meet with a genetic counselor or other health care provider with genetics expertise. If genetic testing is deferred in a child at 50 percent risk, FAP screening is recommended until genetic testing is obtained. (See "Genetic testing", section on 'Ethical, legal, and psychosocial issues' and 'Implications of a pathogenic or likely pathogenic variant' above.)

RESOURCES

UpToDate topics

●Familial adenomatous polyposis (FAP):

•Manifestations and cancer risks – (See "Clinical manifestations and diagnosis of familial adenomatous polyposis".)

•Management – (See "Familial adenomatous polyposis: Screening and management of patients and families".)

●Genetics:

•Variant classification – (See "Basic genetics concepts: DNA regulation and gene expression", section on 'Clinical classification of pathogenicity'.)

•Terminology – (See "Genetics: Glossary of terms".)

•Genetic testing – (See "Genetic testing".)

•Genetic counseling – (See "Genetic counseling: Family history interpretation and risk assessment".)

Locating a genetics expert

●Clinical geneticists – American College of Medical Genetics and Genomics (ACMG)

●Genetic counselors – National Society of Genetic Counselors (NSGC)

●National Institutes of Health (NIH) Cancer Genetics Services Directory