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Testing for FAP/AFAP Overview of testing for FAP/AFAP This overview provides detailed information about genetic testing for familial adenomatous polyposis (FAP) and attenuated familial adenomatous polyposis (AFAP). It is intended to be a reference for providers. Ordering and interpreting genetic testing may be complex and is best done by experienced specialists. When to order genetic testing for FAP/AFAP Screening for all CRC cases • Genetic testing for FAP and AFAP is not recommended for all colorectal cancer (CRC) cases; patients should be tested only if family history and clinical criteria suggest high risk. Screening for high-risk patients and families • To confirm a suspected FAP or AFAP diagnosis in a patient (diagnosis made by clinical criteria), full sequence analysis and/or duplication/deletion analysis of the APC gene should be performed. ■ Full sequencing appears to be more sensitive than deletion/duplication analysis; approximately 90 percent of mutations are detected by full sequencing; 8–12 percent of mutations are detected by deletion/duplication analysis. • Predictive testing for a high-risk (based on family history) asymptomatic patient requires prior identification of the disease-causing mutation in the family. Full sequence analysis and/or duplication/deletion analysis of the APC gene should first be performed on an affected family member, if possible. If the familial mutation is known, then mutationspecific analysis can be performed on the asymptomatic patient. ■ The same approach can be taken with other high-risk asymptomatic family members wishing to be tested. How to interpret genetic testing results Positive result (mutation identified) • A mutation identified in the APC gene is diagnostic for FAP or AFAP (each syndrome is characterized by certain APC mutations). ■ High-risk family members can be tested for the identified mutation ■ Individuals who test positive for the mutation, as well as family members who elect not to be tested, should follow the surveillance guidelines for FAP/AFAP ■ Family members who are tested and found not to carry the identified mutation should follow CRC surveillance guidelines for the general population Colorectal Cancer Fact Sheets: Testing for FAP/AFAP | 1 Testing for FAP/AFAP Negative result (no mutation identified) A negative result (no mutation identified) can be complicated. This result must be interpreted in the context of a patient’s clinical and family history. • If there is a known APC gene mutation in the family, then a negative result is considered a “true negative,” i.e., the patient does not carry the mutation causing FAP or AFAP in other family members. ■ If the patient is asymptomatic, then he or she should follow CRC surveillance guidelines for the general population ■ If the patient has clinical symptoms such as cancer or polyps, the disease-causing mutation is likely sporadic and not within the APC gene; the patient is at increased cancer risk due to personal cancer history ■ In very rare cases, the patient may carry a different APC mutation than that carried by other family members • If there is no known APC gene mutation in the family, a negative result indicates that an APC disease-causing mutation was not identified. However, this negative result may be a “false negative,” i.e., there may still be a mutation present, but the method of testing cannot identify it (test lacks sensitivity), or the testing did not include the APC mutation responsible for cancer predisposition. This result does not provide useful information for testing in relatives. ■ If the patient is asymptomatic, a negative result may be a true negative or a false negative A true negative means that the patient does not carry a disease-causing APC mutation (but this cannot be confirmed without knowing what APC mutation is present in the family) A false negative can mean any of the following: • Family may still carry an APC mutation, but patient may not have inherited it • Method of testing used cannot identify existing mutation • Testing did not include the APC mutation responsible for cancer predisposition in the family Risk is based on clinical and family history ■ If the patient has clinical symptoms such as cancer or colon polyps, a negative result may be a true negative or a false negative A true negative indicates that the patient’s symptoms are not caused by an APC mutation A false negative can mean any of the following: • Family may still carry an APC mutation, but patient’s symptoms are not a result of inheriting it • Method of testing used cannot identify existing mutation • Testing did not include the APC mutation responsible for cancer predisposition in the family The patient is still at high risk of developing additional cancers and other features (such as polyps) associated with FAP and AFAP If an individual has a phenotype like FAP/AFAP, and testing for APC is negative, consider testing for MYH-associated polyposis (MAP), an autosomal recessive colon cancer syndrome Colorectal Cancer Fact Sheets: Testing for FAP/AFAP | 2 Testing for FAP/AFAP Variants of uncertain significance (VOUS) in affected or unaffected individuals • A variation in the normal genetic sequence has been identified, but the causal relationship, if any, to cancer is uncertain (i.e., it is not clear whether the variation is harmful) • Clinical testing of relatives for variants is not recommended • Patient should remain in contact with the testing health care provider and laboratory in case new information clarifies the meaning of the test result • Risks for cancer or cancer recurrence is based on family and clinical history 11-0456:2/12:jt:Updated Feb 2012 Colorectal Cancer Fact Sheets: Testing for FAP/AFAP | 3