BTPS2; DP2; DP2.5; GS; DP3; PPP1R46
The APC gene is associated with autosomal dominant familial adenomatous polyposis (FAP) (MedGen UID: 398651) and attenuated FAP (AFAP) (MedGen UID: 436213).
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APC: Deletion/duplication analysis covers the 1A and 1B promoter regions.
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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 genetic condition that is characterized by the presence of greater than 100 adenomatous colon polyps. On average, individuals with FAP develop polyps at 16 years of age, with 95% of individuals developing polyps by age 35. The risk of developing colon cancer is from 43% to theoretically 100%, if colectomy is not performed (PMID: 18063416, 19822006, 1673441). The average age of colon cancer diagnosis is 39 years, with 93% of untreated individuals diagnosed by age 50 (PMID: 20301519).
FAP may increase the risk of developing other types of non-colonic cancers:
Extra-colonic findings can include extra or missing teeth, desmoid tumors, osteomas, epidermoid cysts, fibromas, and congenital hyperplasia of the retinal pigment epithelium (CHRPE), which is a specific finding that requires a specialized eye examination to identify (PMID: 20301519).
In addition to classic FAP, three subtypes of FAP have been described: Gardner syndrome, Turcot syndrome, and attenuated FAP (AFAP). Gardner syndrome has the same disease progression and risk of colon cancer as classic FAP but is also associated with the development of other extracolonic findings including desmoid tumors, sebaceous cysts, osteomas, supernumerary teeth, and cancer of the duodenum, exocrine pancreas, thyroid (papillary adenocarcinoma), hepatoblastomas, and central nervous system (medulloblastomas). Gardner syndrome was once thought to be a distinct clinical entity; however, like FAP, it is now known to arise from pathogenic variants in APC. Furthermore, with sufficient investigation, subtle extraintestinal manifestations can be found in almost all individuals with FAP (PMID: 20301519).
Similar to Gardner syndrome, Turcot syndrome was once thought to be a distinct clinical entity characterized by the presence of numerous colon adenomas and medulloblastoma. However, it is now assumed that all individuals with an APC pathogenic variant are at increased risk for brain tumors, although the absolute risk is only approximately 1% (PMID: 20301519).
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 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 October 2016). 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 (National Comprehensive Cancer Network, Clinical practice guidelines in oncology®. Genetic/Familial High Risk Assessment: Colorectal). 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
The c.3920T>A (p.Ile1307Lys) variant in APC, also known as I1307K, has been reported as an increased risk allele in association with colorectal cancer. To date, there is no reported association between this APC variant and classic FAP (PMID: 23576677). This variant is present in approximately 6-11% of the Ashkenazi Jewish population and is associated with approximately a 2-fold increased risk of colorectal cancer, particularly in the presence of a family history of colon cancer (PMID: 9288102, 23576677, 20065170, 23896379). Cancer risk in individuals who are not of Ashkenazi Jewish ancestry is unknown (PMID: 23576677). Medical management and surveillance protocols have been suggested by the National Comprehensive Cancer Network (NCCN) for individuals with the I1307K variant (NCCN Clinical Practice Guidelines in Oncology. Genetic/Familial High-Risk Assessment: Colorectal. Version 2.2016):
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.
Review date: October 2016
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, and select noncoding variants. Our assay provides a Q30 quality-adjusted mean coverage depth of 350x (50x minimum, or supplemented with additional analysis). Variants classified as pathogenic or likely pathogenic are confirmed with orthogonal methods, except individual variants that have high quality scores and previously validated in at least ten unrelated samples.
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: Deletion/duplication analysis covers the 1A and 1B promoter regions.