BTPS2; DP2; DP2.5; DP3; GS; PPP1R46
The APC gene is associated with autosomal dominant familial adenomatous polyposis (FAP) (MedGen UID: 398651), attenuated FAP (AFAP) (MedGen UID: 436213), and gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (PMID: 27087319).
Order this gene as a single gene test.
APC: The 1B promoter region is covered by both sequencing and deletion/duplication analysis. The 1A promoter region is covered by deletion/duplication analysis.
Invitae tests that include this gene:
The gene APC (adenomatous polyposis coli) encodes a protein that plays an important role in tumor suppression by antagonizing the Wnt signaling pathway. The Wnt signaling pathway is a regulator of gene transcription and inappropriate activation of this pathway through loss of APC function is known to contribute to cancer progression. APC is also involved in other processes including cell migration, cell adhesion, and apoptosis.
APC – Familial Adenomatous Polyposis
MedGen UID: 398651
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, affected individuals have a lifetime risk of nearly 100% of developing colorectal cancer (PMID: 18063416, 19822006, 1673441).
Gastric adenocarcinoma and proximal polyposis of the stomach (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 (PMID: 21643010, 25243319, 25941542, 23725351, 24946964).
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 (PMID: 20301519).
FAP may increase the risk of developing other types of non-colonic cancers:
Attenuated FAP (AFAP) has a later age of onset than classic FAP (approximately 50 years of age), presents with fewer adenomatous polyps (<100) that are primarily proximal (right-sided), and has an overall lower lifetime risk of developing colorectal cancer of approximately 70% (PMID: 18063416, 19822006, 1673441, 20301519).
APC is a tumor suppressor gene that acts as an antagonist of the Wnt signaling pathway. It is also involved in other processes including cell migration and adhesion, transcriptional activation, and apoptosis (NCBI Gene. Gene ID: 324. http://www.ncbi.nlm.nih.gov/gene/324. Accessed February 2018). If there is a pathogenic variant in this gene that prevents it from normally functioning, there is an increased risk to develop certain types of cancers.
FAP has autosomal dominant inheritance. This means that an individual with a pathogenic variant has a 50% chance of passing the condition on to their offspring. With this result, it is now possible to identify at-risk relatives who can pursue testing for this specific familial variant. While many cases are inherited from a parent, some occur spontaneously (PMID: 8199592). This means that an individual with a pathogenic variant has parents who do not have it. However, that individual now has a 50% risk of passing it on to future offspring.
Medical management and surveillance protocols have been developed by the National Comprehensive Cancer Network (NCCN) for individuals with FAP and AFAP (NCCN Clinical Practice Guidelines in Oncology®: Genetic/Familial High Risk Assessment: Colorectal. Version 3.2017). These recommendations apply to individuals diagnosed with FAP and AFAP based on clinical findings or genetic test results, as well as individuals at an increased risk based on family history who have not had negative genetic testing:
Variant Specific Management for the I1307K Variant
UNAFFECTED INDIVIDUALS: If there is no personal history of colorectal cancer but there is a diagnosis of colorectal cancer in a first-degree relative, colonoscopy is recommended every 5 years beginning at age 40, or 10 years prior to the first-degree relative’s age at diagnosis. If there is no personal history of colorectal cancer and no diagnosis of colorectal cancer in a first-degree relative, colonoscopy is recommended every 5 years beginning at age 40.
AFFECTED INDIVIDUALS: Patients with colon cancer and this variant should follow guidelines post cancer resection
An individual’s cancer risk and medical management are not determined by genetic test results alone. Overall cancer risk assessment incorporates additional factors, including personal medical history, family history, and any available genetic information that may result in a personalized plan for cancer prevention and surveillance.
It is advantageous to know if an individual has a pathogenic variant in APC as medical management recommendations can be implemented. At-risk relatives can be identified, allowing pursuit of a diagnostic evaluation. In addition, the available information regarding hereditary cancer susceptibility genes is constantly evolving and more clinically relevant APC data are likely to become available in the near future. Awareness of this cancer predisposition encourages patients and their providers to inform at-risk family members, to diligently follow standard screening protocols, and to be vigilant in maintaining close and regular contact with their local genetics clinic in anticipation of new information.
Referenced with permission from the NCCN Genetic/Familial High-Risk Assessment: Colorectal. Version 3.2017. © National Comprehensive Cancer Network, Inc. 2016. All rights reserved. Accessed February 2018. To view the most recent and complete version of the guideline, go online to NCCN.org.
The NCCN Guidelines are a work in progress that may be refined as often as new significant data becomes available. The NCCN Guidelines® are a statement of consensus of its authors regarding their views of currently accepted approaches to treatment. Any clinician seeking to apply or consult any NCCN Guidelines® is expected to use independent medical judgment in the context of individual clinical circumstances to determine any patient’s care or treatment. The National Comprehensive Cancer Network makes no warranties of any kind whatsoever regarding their content, use or application and disclaims any responsibility for their application or use in any way.
Review date: February 2018
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. In addition, the analysis covers the select non-coding variants specifically defined in the table below. 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.