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APC

Alias

BTPS2; DP2; DP2.5; DP3; GS; PPP1R46

Associated disorders

The APC gene is associated with APC-associated polyposis conditions, which include gastric adenocarcinoma and proximal polyposis of the stomach (GAPPS) (MedGen UID: 798250 ), familial adenomatous polyposis (FAP) (MedGen UID: 398651), and attenuated FAP (AFAP) (MedGen UID: 436213).

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APC

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APC: The 1B promoter region is covered by both sequencing and deletion/duplication analysis. The 1A promoter region is covered by deletion/duplication analysis.


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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

Clinical condition
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).

Gene information
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.

Inheritance
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.

Management
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:

Classic FAP
Colon:

  • Annual sigmoidoscopy/colonoscopy beginning at 10-15 years of age.
  • A colectomy or proctocolectomy is recommended after numerous polyps are detected, due to their high malignant potential. Total proctocolectomy with ileal pouch-anal anastomosis (IPAA) is generally the recommended surgical approach for individuals with FAP.
  • If colectomy with ileorectal anastomosis (IRA) is performed, endoscopic evaluation of the remaining rectum is recommended every 6-12 months depending on polyp burden.
  • If total proctocolectomy with IPAA or ileostomy is performed, endoscopic evaluation of the ileal pouch or ileostomy is recommended every 1-3 years depending on polyp burden. If large, flat polyps with villous histology or polyps with high-grade dysplasia are identified, then surveillance frequency should be every 6 months.
  • Chemoprevention (e.g., sulindac) can aid in management of the remaining rectum; however, there are no medications currently approved by the FDA for this indication. There are data to suggest that sulindac showed the most significant polyp regression, but it is unclear if the decrease in polyp burden equates to reduction in colorectal cancer risk.

Extracolonic:
  • Upper endoscopy with complete visualization of the ampulla of Vater beginning at age 20-25 years.
    • Consider upper endoscopy at an earlier age if colectomy is performed prior to 20 years of age. Frequency of upper endoscopy surveillance is dependent on polyp burden. It is important to note that fundic gland polyps are common in individuals with FAP and while focal low-grade dysplasia can be identified, it is typically non-progressive. Non-fundic gland polyps should be managed endoscopically if possible. Polyps with high-grade dysplasia or invasive cancer detected on biopsy should be referred for gastrectomy.
  • Annual thyroid examination beginning in the late teenage years. Annual thyroid ultrasound may be considered, but data are lacking to support this recommendation.
  • Annual physical examination for CNS cancers.
  • Annual abdominal palpation for desmoids.
    • If there is family history of symptomatic desmoids, consider abdominal MRI or CT within 1–3 years post-colectomy, then every 5–10 years. Abdominal symptoms should prompt immediate abdominal imaging; however, data to support screening and treatment are limited. For small bowel polyps and cancer, consider adding small bowel visualization to MRI or CT for desmoids especially, if duodenal polyposis is advanced
  • Consider liver palpation, abdominal ultrasound, and measurement of AFP every 3-6 months during the first 5 years of life to screen for hepatoblastoma.

AFAP
Colon:

  • Colonoscopy beginning in the late teens, then every 2-3 years.
    • If a small polyp burden is found, repeat colonoscopy with polypectomy every 1-2 years.
      • If polyp burden is too great, consider colectomy with ileorectal anastomosis (IRA) or proctocolectomy with ileal pouch-anal anastomosis (IPAA) if rectal polyposis is not manageable with polypectomy. Following colectomy with IRA, endoscopic evaluation of the remaining rectum is recommended every 6–12 months depending on polyp burden. Chemoprevention (e.g., sulindac) can aid in management of the remaining rectum; however, there are no medications currently approved by the FDA for this indication. There are data to suggest that sulindac showed the most significant polyp regression, but it is unclear if the decrease in polyp burden equates to reduction in colorectal cancer risk.

Extracolonic:
  • Annual physical examination.
  • Annual thyroid examination.
  • Upper endoscopy with complete visualization of the ampulla of Vater beginning at around age 20-25 years. Consider upper endoscopy at an earlier age if colectomy is performed prior to 20 years of age. Frequency of upper endoscopy surveillance is dependent on polyp burden.

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.

Additional reference
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

Assay and technical information

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, +/- 10 base pairs of adjacent intronic sequence in the transcript listed below. In addition, analysis covers the select non-coding variants specifically defined in the table below. Any variants that fall outside these regions are not analyzed. Any specific limitations in the analysis of these genes are also listed in the table below.

Our analysis detects most intragenic deletions and duplications at single exon resolution. However, in rare situations, single-exon copy number events may not be analyzed due to inherent sequence properties or isolated reduction in data quality. If you are requesting the detection of a specific single-exon copy number variation, please contact Client Services before placing your order.

Gene Transcript reference Sequencing analysis Deletion/Duplication analysis
APC* NM_000038.5


*APC: The 1B promoter region is covered by both sequencing and deletion/duplication analysis. The 1A promoter region is covered by deletion/duplication analysis.