This test analyzes the APC gene. Pathogenic variants in this gene can cause APC-associated polyposis conditions, which include familial adenomatous polyposis (FAP), attenuated FAP (AFAP), and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS). These disorders are primarily associated with the development of numerous colon polyps and colon cancer.
Genetic testing of this gene may confirm a diagnosis and help guide treatment and management decisions. Identification of a disease-causing variant would also guide testing and diagnosis of at-risk relatives. This test is specifically designed for heritable germline mutations and is not appropriate for the detection of somatic mutations in tumor tissue.
APC can also be ordered as part of a broader panel to test for different types of hereditary cancer, including colorectal and pancreatic cancers. Depending on an individual’s clinical and family history, one of these broader panels may be appropriate. Any of these broader panels can be ordered at no additional charge.
Familial adenomatous polyposis (FAP) is a colorectal cancer predisposition syndrome characterized by the development of hundreds to thousands of precancerous (adenomatous) polyps, typically beginning in adolescence or early adulthood. Without a prophylactic colectomy, individuals with FAP have a lifetime risk of nearly 100% for developing colorectal cancer. AFAP has a later age of onset than classic FAP, presents with fewer adenomatous polyps (<100), and has an overall lower lifetime risk of developing cancer (approximately 70%).
GAPPS is characterized by fundic gland polyposis and an increased risk of gastric cancer (gastric adenocarcinoma). Polyps are often associated with low-grade and focally high-grade dysplasia. Unlike other pathogenic variants in APC, the risk of colorectal polyposis and cancer appears to be lower. GAPPS is caused by pathogenic variants in promoter 1B of the APC gene, which this test analyzes.
FAP was previously divided into subtypes including Turcot and Gardner syndromes. These subtypes were defined by the presence of certain extracolonic findings such as desmoid tumors, sebaceous cysts, osteomas, supernumerary teeth, and cancers of the duodenum, exocrine pancreas, thyroid (papillary adenocarcinoma), liver (hepatoblastomas), and central nervous system (medulloblastomas). It is now recognized that these subtypes are part of the clinical spectrum of APC-associated polyposis conditions.
FAP is a highly penetrant condition. If it is left untreated, affected individuals have a lifetime risk of nearly 100% of developing colorectal cancer. For AFAP, the lifetime risk for colorectal cancer is 70%. GAPPS-associated cancer risks are currently unknown. See the table below for FAP-associated cancer risks:
|Cancer type||Cancer risk|
|Colon||Up to 100% (70% for attenuated FAP)|
|Sarcoma||Up to 25%|
|Hepatoblastoma (up to age 5)||1%-2%|
|Gastric||Up to 0.5%|
Sequencing of the APC gene identifies a pathogenic variant in up to 90% of individuals with a clinical diagnosis of FAP; deletion/duplication analysis identifies an additional 8-12% of cases. The clinical sensitivity for GAPPS is currently uncertain.
APC-associated polyposis conditions are inherited in an autosomal dominant pattern. Most cases are inherited from a parent; however, up to 25% of cases are due to a spontaneous de novo mutation.
APC-associated polyposis conditions historically accounted for approximately 0.5% of all colorectal cancer, but this number is decreasing with increased awareness, early detection and intervention. Collectively, the APC-associated polyposis conditions have a prevalence of approximately 2-3 in 100,000 individuals.
Clinical testing for FAP/AFAP should be considered in individuals with:
Clinical testing for GAPPS should be considered in individuals with:
For management recommendations, please refer to:
Invitae is a College of American Pathologists (CAP)-accredited and Clinical Laboratory Improvement Amendments (CLIA)-certified clinical diagnostic laboratory performing full-gene sequencing and deletion/duplication analysis using next-generation sequencing technology (NGS).
Our sequence analysis covers clinically important regions of each gene, including coding exons and 10 to 20 base pairs of adjacent intronic sequence on either side of the coding exons in the transcript listed below, depending on the specific gene or test. In addition, the analysis covers select non-coding variants. Any variants that fall outside these regions are not analyzed. Any limitations in the analysis of these genes will be listed on the report. Contact client services with any questions.
Based on validation study results, this assay achieves >99% analytical sensitivity and specificity for single nucleotide variants, insertions and deletions <15bp in length, and exon-level deletions and duplications. Invitae's methods also detect insertions and deletions larger than 15bp but smaller than a full exon but sensitivity for these may be marginally reduced. Invitae’s deletion/duplication analysis determines copy number at a single exon resolution at virtually all targeted exons. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. Certain types of variants, such as structural rearrangements (e.g. inversions, gene conversion events, translocations, etc.) or variants embedded in sequence with complex architecture (e.g. short tandem repeats or segmental duplications), may not be detected. Additionally, it may not be possible to fully resolve certain details about variants, such as mosaicism, phasing, or mapping ambiguity. Unless explicitly guaranteed, sequence changes in the promoter, non-coding exons, and other non-coding regions are not covered by this assay. Please consult the test definition on our website for details regarding regions or types of variants that are covered or excluded for this test. This report reflects the analysis of an extracted genomic DNA sample. In very rare cases, (circulating hematolymphoid neoplasm, bone marrow transplant, recent blood transfusion) the analyzed DNA may not represent the patient's constitutional genome.
|Gene||Transcript reference||Sequencing analysis||Deletion/Duplication analysis|
APC: The 1B promoter region is covered by both sequencing and deletion/duplication analysis. The 1A promoter region is covered by deletion/duplication analysis. Sequencing analysis for exons 5 includes only cds +/- 10 bp.