YES NO UNKNOWN. Stage I: Rule-Out Dashboard ACTIONABILITY PENETRANCE SIGNIFICANCE/BURDEN OF DISEASE NEXT STEPS. YES ( 1 of above)

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1 Stage I: Rule-Out Dashboard GENE/GENE PANEL: SMAD4, BMPR1A DISORDER: Juvenile Polyposis Syndrome HGNC ID: 6670, 1076 OMIM ID: , ACTIONABILITY PENETRANCE 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? Yes No Patient Management Surveillance or Screening 4. Is there at least one known pathogenic variant with at least moderate penetrance ( 40%) or moderate relative risk ( 2) in any population? UNKWN SIGNIFICANCE/BURDEN OF DISEASE 5. Is this condition an important health problem? Family Management Circumstances to Avoid ( 1 of above) NEXT STEPS 6. Are Actionability (Q2-3), Penetrance (Q4), and Significance (Q5) all? 3. Is the result actionable in an undiagnosed adult with the genetic condition? (Proceed to Stage II) (Consult Actionability Working Group) Exception granted, proceed to Stage II Exception not granted, STOP 1

2 GENE/GENE PANEL: SMAD4, BMPR1A DISORDER: Juvenile Polyposis Syndrome Topic Narrative Description of Evidence Ref Signif/Burden of Condition 1. What is the nature of the threat to health for an individual carrying a deleterious allele? Prevalence of the genetic disorder Clinical Features (Signs/symptoms) Natural History (Important subgroups & survival/recovery) Robust prevalence estimates for Juvenile polyposis syndrome (JPS) are not available because of its rarity, the lack of comprehensive clinical phenotype ascertainment and the fact that there are no population-based molecular studies. However, estimates of the population prevalence suggest the frequency of JPS may be similar to that of Peutz-Jeghers syndrome suggesting a frequency of around 1:50,000, although it may be as low as 1:120,000. JPS is characterized by predisposition to hamartomatous polyps in the gastrointestinal tract, specifically in the stomach, small intestine, colon, and rectum. Histological differences and topographical distribution within the gastrointestinal tract serve to distinguish between JPS and Peutz-Jeghers Syndrome. The number of polyps in individuals with JPS varies, with dozens to many hundreds of polyps present in the fully developed syndrome. A combined syndrome of JPS and hereditary hemorrhagic telangiectasia (HHT) (termed JPS/HHT) is present in most individuals with an SMAD4 pathogenic variant. [Hereditary hemorrhagic telangiectasia is addressed in a separate report] The term juvenile refers to the polyp type rather than to the age of onset, although most individuals with JPS have some polyps by 20 years of age. JPS usually manifests during childhood with polyps beginning to appear in the first decade of life. The average age at diagnosis is 18.5 years, but may be later, with rectal bleeding with anemia as the most common presenting symptom. Most juvenile polyps are benign; however, malignant transformation can occur. In those who develop cancer, the mean age of colon cancer is 34 years, with a range of 15 to 68 years and the median age of upper GI cancer is 58 years with a range of 21 to 73 years. 2. How effective are interventions for preventing the harm? Information on the effectiveness of the recommendations below was not provided unless otherwise stated. To determine the extent of disease, a baseline evaluation of patients should include a clinical history, complete blood count, colonoscopy, and upper endoscopy. (Tier 3) (1) Patient Management Surveillance Colectomy and ileorectal anastomosis or proctocolectomy and ileal pouch-anal anastomosis is indicated for polyp-related symptoms, or when the polyps cannot be managed endoscopically. One case series reported on long-term outcomes of colonic surgery in 13 patients presenting with symptomatic colon polyps (median age at diagnosis=10 years, range=1-50 years). Eight patients had their rectum removed during the study period; 5 had an ileal pouch-anal anastomosis, one had a Koch pouch as a restorative surgery, and 2 had an end ileostomy. No relation was observed between the number of colonic and rectal polyps and the type of surgery or the need for proctectomy. Patients were followed up a median of 3 years (range=2-24 years) after their ultimate operations. During this period, one patient (20%) who underwent restorative proctectomy and 4 patients (80%) whose rectums were preserved required multiple endoscopic polypectomies for recurrent polyps in the pouch (first patient) or their rectums (the other 4 patients). The patient who underwent the Koch procedure required surgery for recurrent polyps in her pouch.(tier 2) Colonoscopy is recommended in patients with JPS. Recommended starting age ranges across guidelines from 12-18, while frequency ranges from annually to every 3 years. The frequency of screening may be determined by the findings of the previous endoscopy, and may be extended to longer intervals after age 35. There are no comparative studies to demonstrate the potential benefit of screening; however, there is substantial risk of CRC in JPS patients. The life-time risk of CRC death in JPS patients not undergoing surveillance is (1, 2, 4, 5) 2

3 estimated to be as high as 1 in 6. ) One retrospective review of a registry of 44 patients with JPS undergoing routine surveillance (380 patient-years follow up) of the upper and lower GI tract has reported surveillance results. Screening detected 767 polyps and 20 adenomatous polyps. Five patients were identified requiring colorectal surgery. Two patients developed colorectal cancer while undergoing surveillance. However, given the lack of a control group it is unclear how many of these patients would have been detected clinically without undergoing surveillance.(tier 2) Family Management Circumstances to Avoid Upper endoscopy is also recommended in patients with JPS. Recommended starting age ranges across guidelines from years, while frequency ranges from annually to every 3 years. The frequency of screening is determined by the findings of the previous endoscopy, and may be extended to longer intervals after age 35. The risk of gastric and duodenal cancer in JPS is around 15-21%. Among the retrospective registry of JPS patients, gastrodueodenal polyps were found in 37% of patients and two patients were identified with adenomatous polyps of the stomach. Two patients were identified requiring gastrectomy. One patient developed cancer while undergoing surveillance. However, given the lack of a control group it is unclear how many of these patients would have been detected clinically without undergoing surveillance.(tier 2) Periodic enteroscopy, capsule endoscopy and/or CT enterography may be used for surveillance of the small intestine. (Tier 2) A case series of small-bowel capsule endoscopy of ten adults (median age 39.2 years) with documented JPS identified 2 patients that had small-bowel polyps beyond the range of standard gastroscopy identified at capsule endoscopy. Duodenal polyps were detected in a third patient at capsule endoscopy not previously detected by standard gastroscopy. However, given the lack of a control group it is unclear how many of these patients would have been detected clinically without undergoing surveillance (Tier 5) Genetic testing should be performed on at-risk family members in the first to second decade of life to identify those who will benefit from early surveillance intervention. (Tier 4) Relatives of individuals with an identified SMAD4 or BMPR1A pathologic variant who have not undergone molecular genetic testing or whose tests results were uninformative should undergo monitoring for stool change. In addition these patients should receive a complete blood count, colonoscopy and upper endoscopy starting in the mid-teens or at time of symptoms. The frequency of subsequent screening depends on the number of polyps identified on endoscopic screening. (Tier 3) For relatives not found to have a family specific genetic variant, CBC and lower initial endoscopy should be performed at age 15 years as a baseline screen, and if negative, repeated every ten years until age 45 after which time standard CRC screening recommendations may be followed. (Tier 3) None identified (1, 2, 4, 5) (2, 4) (6) Description of sources of evidence: 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 3

4 GENE/GENE PANEL: DISORDER: Topic Narrative Description of Evidence Ref 3. What is the chance that this threat will materialize? Mode of Inheritance Autosomal Dominant Prevalence of Genetic Mutations No estimates were identified for the prevalence of SMAD4 or BMPR1A mutations. Up to 60% of individuals with a clinically defined JPS are found to exhibit mutations of the SMAD4 or BMPR1A genes.(tier 3) No studies have examined the proportion of individuals with known germline pathogenic variants for JPS who develop polyps. It is expected to be higher than 90%. (Tier 4) Penetrance OR Relative Risk (include high risk racial or ethnic subgroups) Estimates for the risk of colorectal cancer range from 10-68%, though a more recent synthesis estimates a range of 38-68%. (Tier 3) An estimated 21% of patients with JPS will develop upper gastrointestinal cancer. (Tier 3) (1, 2) The relative risk of developing colorectal cancer was found to be 34.0 (14.4 to 65.7). (Tier 3) Expressivity The number of polyps in individuals with JPS varies. Some individuals may have only four or five polyps over their lifetime; others in the same family may have more than 100. (Tier 4) 4. What is the nature of the intervention? Nature of Intervention Identified interventions include upper and lower gastrointestinal surveillance. 5. Would the underlying risk or condition escape detection prior to harm in the setting of recommended care? Chance to Escape Clinical Detection The average age at diagnosis is 18.5 years, but may be later, with rectal bleeding with anemia as the most common presenting symptom. (Tier 3) Final Consensus Scores Gene(s) Outcome/intervention pair Severity Likelihood Effectiveness Nature of the Intervention SMAD4 GI cancer/endoscopic surveillance 2 3C 3E 2 10CE To see the scoring key, please go to: Total Score 4

5 Date of Search: ( ) References 1. Cairns SR, Scholefield JH, Steele RJ, Dunlop MG, Thomas HJ, Evans GD, et al. Guidelines for colorectal cancer screening and surveillance in moderate and high risk groups (update from 2002). Gut. 2010;59(5): Syngal S, Brand RE, Church JM, Giardiello FM, Hampel HL, Burt RW. ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. The American journal of gastroenterology. 2015;110:223-62; quiz Larsen Haidle J, Howe JR. Juvenile Polyposis Syndrome. GeneReviews(R) National Comprehensive Cancer Network. Genetic/Familial High-Risk Assessment: Colorectal (Version ) 2015 [October 7, 2015]. Available from: 5. Scottish Intercollegiate Guidelines Network. Diagnosis and management of colorectal cancer. A national clinical guideline. Edinburgh (Scotland): 2011 no Postgate AJ, Will OC, Fraser CH, Fitzpatrick A, Phillips RK, Clark SK. Capsule endoscopy for the small bowel in juvenile polyposis syndrome: a case series. Endoscopy. 2009;41(11):