Stage I: Binning Dashboard GENE/GENE PANEL: APC ACTIONABILITY 1. Is there a qualifying resource, such as a practice guideline or systematic review, for the genetic condition? 2. Does the practice guideline or systematic review indicate that the result is actionable in one or more of the following ways? DISORDER: Classical Familial adenomatous polyposis (FAP) PENETRANCE 4. Is there at least one known pathogenic variant with at least moderate penetrance ( 40%) or moderate relative risk ( 2) in any population? SIGNIFICANCE/BURDEN OF DISEASE Yes No 5. Is this condition an important health problem? Patient Management Surveillance or Screening Family Management NEXT STEPS Circumstances to Avoid ( 1 of above) 3. Is the result actionable in an undiagnosed adult with the genetic condition? 6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5) all? (Proceed to Stage II) (Consult Actionability Working Group) Exception granted, proceed to Stage II Exception not granted, STOP
Signif/Burden of Condition GENE/GENE PANEL: APC DISORDER: Classical Familial adenomatous polyposis (FAP) Topic Narrative Description of Evidence Ref 1. What is the nature of the threat to health for an individual carrying a deleterious allele? Prevalence of the genetic disorder Approximately 4.8% of men and women will be diagnosed with colorectal cancer (CRC) in their lifetime. There are an estimated 1.1 million people currently living with CRC in the U.S. Familial adenomatous polyposis (FAP) accounts for 1% of CRC cases. [1] [2-4] Clinical Features FAP is characterized by the development of hundreds to thousands of adenomas in the colorectum; classical FAP is based on the presence of 100 polyps. Extracolonic manifestations are variably present and include desmoid tumors and other malignancies. [2-8] [3-9] Natural History Colorectal adenomatous polyps begin to appear, on average, by age 16. By age 35, 95% of FAP patients have polyps. In virtually all cases, the adenomas will develop into CRC if left untreated. The mean age of CRC diagnosis in untreated individuals is 39 years; 93% of untreated patients develop CRC by age 50. 2. How effective are interventions for preventing the harm? Patient Management It is recommended that carriers of the APC mutation be referred for genetic counseling, and be followed by a GI specialist. (Tier 2) Prophylactic (procto)colectomy is recommended when the number and size of the polyps impede surveillance of the colon. The chance of rectal carcinoma after ileorectal anastomosis (IRA) is estimated to be 12-43%, depending on endoscopic surveillance. The chance of adenomas in the pouch following ileal pouch-anal anastomosis (IPAA) ranges from 8-62%, depending on surveillance. (Tier 2) Non-aspirin NSAIDs may be effective for reducing the number and size of colorectal polyps and adenomas in individuals with FAP. NSAIDs use has resulted in a 7-30% decrease in rectal polyps following IRA. (Tier 1) Registry-based screening of individuals with FAP has been shown to lead to a reduction in CRC incidence and CRC-related mortality. Odds ratios for CRC incidence following registration range from 0.09-0.44. Odds ratios for CRC-related mortality range from 0.11-0.22. (Tier 1) [2-6] [9-13] [3;4;9; 10;12] [3;14;1 5] [2] Surveillance Family Management Circumstances to Avoid Endoscopic surveillance for colorectal polyps, adenomas, and/or CRC is recommended annually or semiannually, until colectomy. CRC incidence was found to be 3-10% among cases identified through surveillance, compared to 50-70% in symptomatic FAP cases. (Tier 2) Regular endoscopic surveillance of the duodenum is advised. However, the efficacy of this surveillance in reducing CRC incidence is not known. (Tier 1) Additional surveillance may include: annual thyroid exam, annual physical exam with a focus on central nervous system disorders, annual abdominal palpation. However, these screening methods have not been shown to be effective in reducing CRC incidence. (Tier 2) At-risk family members are encouraged to undergo colorectal screening starting by puberty; genetic testing is recommended to clarify risks. (Tier 2) First degree relatives should be followed by a gastroenterologist. (Tier 2) No recommendations were identified. [3;4;9-11;16-20] [3] [9] [3;9;10; 13;17-20] [13]
GENE/GENE PANEL: APC DISORDER: Classical Familial adenomatous polyposis (FA) Topic Narrative Description of Evidence Ref 3. What is the chance that this threat will materialize? Mode of Inheritance Prevalence of Genetic Mutations Penetrance OR Relative Risk Autosomal dominant APC mutations occur in 1 in 10,000 births. (Tier 3) APC mutations can be identified in 80-93% of FAP cases. (Tier 3) [4] [3;21] Virtually 100% of untreated individuals with FAP will develop CRC. (Tier 3) [2-4;6;18; 22] No relative risk estimates were identified. Expressivity Development of colorectal adenomas is variable, including variability in the number of adenomas within families with the same APC mutation; 50% of patients have polyps by age 15-16, and 95% by 35 years of age. The presence of duodenal adenomas ranges from 33-92%; 26-51% of FAP patients develop stomach polyps. (Tier 3) Desmoid tumors occur in 10-25% of FAP cases. (Tier 3) Both inter- and intrafamilial phenotypic variability are common. (Tier 3) 4. What is the nature of the intervention? Nature of Intervention Endoscopic surveillance is burdensome for individuals. (Tier 4) NSAIDs may be associated with an increased risk of serious cardiovascular events, particularly in patients with pre-existing cardiovascular risk factors. NSAIDs can also cause upper gastrointestinal toxicity. (Tier 1) There is a small but appreciable risk of complications from colonoscopy including perforation, bleeding, and death. (Tier 3) (Procto)Colectomy is associated with possible intra- and post-operative complications. 5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care? Chance to Escape Clinical Detection General population CRC screening is recommended at age 50. Given the early age of development of adenomas and CRC in FAP patients, general population screening would not allow for prophylactic measures to be taken. (Tier 1) [3;6] [5] [3;21] [14] [10] [16] Tier 1: Evidence from a systematic review, or a meta-analysis or clinical practice guideline clearly based on a systematic review Tier 2: Evidence from clinical practice guidelines or broad-based expert consensus with non-systematic evidence review Tier 3: Evidence from another source with non-systematic review of evidence with primary literature cited Tier 4: Evidence from another source with non-systematic review of evidence with no citations to primary data sources Tier 5: Evidence from a non-systematically identified source
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