Familial Adenomatous Polyposis (FAP) Mutation Screen
Clinical Information Discusses physiology, pathophysiology, and general clinical aspects, as they relate to a laboratory test
Familial adenomatous polyposis (FAP) is an autosomal dominant condition caused by mutations in the APC gene located on the long arm of chromosome 5 (5q21). Classic FAP is characterized by progressive development of hundreds to thousands of adenomatous colon polyps. Polyps may develop during the first decade of life and the majority of untreated FAP patients will develop colon cancer by age 40. Typically, there is a predominance of polyps on the left side of the colon, however other areas of the colon may also be affected. The presence of extracolonic manifestations is variable and includes gastric and duodenal polyps, ampullary polyps, osteomas, dental abnormalities (unerupted teeth), congenital hypertrophy of the retinal pigment epithelium (CHRPE), benign cutaneous lesions, desmoids tumors, hepatoblastoma, and extracolonic cancers. Common constellations of colonic and extracolonic manifestations have resulted in the designation of 3 clinical variants: Gardner syndrome, Turcot syndrome, and hereditary desmoid disease.
Gardner syndrome is characterized by colonic polyps of classic FAP with epidermoid skin cysts and benign osteoid tumors of the mandible and long bones. Turcot syndrome is characterized by multiple colonic polyps and central nervous system (CNS) tumors.
Turcot syndrome is an unusual clinical variant of FAP, as it is also considered a clinical variant of hereditary nonpolyposis colorectal cancer (HNPCC). Individuals with Turcot syndrome have CNS tumors in addition to adenomatous polyps. The types of CNS tumor observed helps to distinguish Turcot-FAP variant patients from Turcot-HNPCC variant patients. The predominant CNS tumor associated with the Turcot-FAP variant is medulloblastoma, while glioblastoma is the predominant CNS tumor associated with Turcot-HNPCC.
Hereditary desmoid disease (HDD) is a variant of FAP with multiple desmoids tumors as the predominant feature. Many patients with HDD may not even show colonic manifestations of FAP. APC germline testing may assist clinicians in distinguishing a sporadic desmoid tumor, from that associated with FAP.
Attenuated FAP (AFAP) is characterized by later onset of disease and a milder phenotype (typically <100 adenomatous polyps and fewer extracolonic manifestations) than classic FAP. Typically individuals with AFAP develop symptoms of the disease at least 10 to 20 years later than classically affected individuals. Individuals with AFAP often lack a family history of colon cancer and/or multiple adenomatous polyps. Of note, clinical overlap is observed between AFAP and MYH-associated polyposis (MAP), an autosomal recessive polyposis syndrome typically associated with fewer than 100 polyps. Although the clinical phenotype of MAP remains somewhat undefined, extracolonic manifestations, including CHRPE have been described in affected patients. Given the phenotypic overlap of AFAP and MAP, these tests are commonly ordered together or in a reflex fashion.
See Colorectal Adenomatous Polyposis Algorithm in Special Instructions for additional information. Also see Hereditary Colorectal Cancer: Adenomatous Polyposis Syndromes (September 2004 Communique') in Publications for additional information.
Confirmation of familial adenomatous polyposis (FAP) diagnosis for patients with clinical features
This test should be ordered only for individuals with symptoms suggestive of FAP. Asymptomatic patients with a family history of FAP should not be tested until a mutation has been identified in an affected family member.
All detected alterations are evaluated according to American College of Medical Genetics (ACMG) recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance.
Cautions Discusses conditions that may cause diagnostic confusion, including improper specimen collection and handling, inappropriate test selection, and interfering substances
Some individuals who are carriers or have a diagnosis of familial adenomatous polyposis (FAP) may have a mutation that is not identified by this method (eg, promoter mutations, deep intronic alterations). The absence of a mutation, therefore, does not eliminate the possibility of positive carrier status or the diagnosis of FAP. For predictive testing of asymptomatic individuals, it is important to first document the presence of an APC gene mutation in an affected family member.
Test results should be interpreted in the context of clinical findings, family history, and other laboratory data. Errors in our interpretation of results may occur if information given is inaccurate or incomplete.
In some cases, DNA variants of undetermined significance may be identified. Due to the limitations of next generation sequencing, we can detect 90% of insertions and deletions up to 28 bases and 38 bases, respectively. If a diagnosis is still suspected, consider full gene sequencing using traditional Sanger methods. Single or multi-exon deletions as well as whole gene deletions will be detected by multiplex ligation-dependent probe amplification (MLPA). Rare polymorphisms exist that could lead to false-negative or false-positive results. If results obtained do not match the clinical findings, additional testing should be considered.
In addition to disease-related probes, the MLPA technique utilizes probes localized to other chromosomal regions as internal controls. In certain circumstances, these control probes may detect other diseases or conditions for which this test was not specifically intended. Results of the control probes are not normally reported. However, in cases where clinically relevant information is identified, the ordering physician will be informed of the result and provided with recommendations for any appropriate follow-up testing.
A previous bone marrow transplant from an allogenic donor will interfere with testing. Call Mayo Medical Laboratories for instructions for testing patients who have received a bone marrow transplant.
Multiple in-silico evaluation tools were used to assist in the interpretation of these results. These tools are updated regularly; therefore, changes to these algorithms may result in different predictions for a given alteration. Additionally, the predictability of these tools for the determination of pathogenicity is currently not validated.
Unless reported or predicted to cause disease, alterations found deep in the intron or alterations that do not result in an amino acid substitution are not reported. These and common polymorphisms identified for this patient are available upon request.
Reclassification of Variants-Policy:
All detected alterations are evaluated according to American College of Medical Genetics and Genomics recommendations.(1) Variants are classified based on known, predicted, or possible pathogenicity and reported with interpretive comments detailing their potential or known significance. At this time, it is not standard practice for the laboratory to systematically review likely deleterious alterations or variants of uncertain significance that are detected and reported. The laboratory encourages health care providers to contact the laboratory at any time to learn how the status of a particular variant may have changed over time.
Reference Values Describes reference intervals and additional information for interpretation of test results. May include intervals based on age and sex when appropriate. Intervals are Mayo-derived, unless otherwise designated. If an interpretive report is provided, the reference value field will state this.
An interpretive report will be provided.
Clinical References Provides recommendations for further in-depth reading of a clinical nature
1. Richards CS, Bale S, Bellissimo DB, et al: ACMG recommendations for standards for interpretation and reporting of sequence variations: Revisions 2007. Genet Med 2008:10(4):294-300
2. American Society of Clinical Oncology. American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility. Clin Oncol 2003;21:2397-2406
3. Half E, Bercovich D, Rozen P: Familial adenomatous polyposis. Orphanet J Rare Dis 2009 Oct 12;4:22
4. Croner RS, Brueckl WM, Reingruber B, et al: Age and manifestation related symptoms in familial adenomatous polyposis. BMC Cancer 2005 Mar 2;5:24