{ "@context": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/context/doc", "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025", "id": "CG-AC:AC025", "type": "ClinicalActionabilityReport", "metadata": { "schemaLabel": "AC-Sepio.Beta-1 (Unofficial)", "contentVersionId": "26339", "producedAtUTC": "Thu, 10 Sep 2026 19:39:24 -0000", "note": "DISCLAIMER: The SEPIO-inspired schema presented here is an initial prototype for Clinical Actionability curation summaries and has not been reviewed nor finalized by the ClinGen Data Exchange Modeling Team. We expect it to differ significantly from the final schema." }, "description": "JSON-LD representation of ClinGen Actionability Stage 2 report modeled with SEPIO. The hierarchically structured document will include:\n1. Contextual & topic information, such as the **conditions/diseases** and the **genes**.\n2. Categorized **evidence narratives**, with references.\n\t* This content corresponds to the texts within the *Actionability Summary Report*\n4. **Outcome & Intervention** pairs, with **consensus scoring** in 5 dimensions:\n\t1. Outcome Severity\n\t2. Outcome Likelihood\n\t3. Intervention Effectiveness\n\t4. Nature of the Intervention\n\t5. Total (Overall) Score\n\n*( Note: The summary report does not include the **Screening Survey** which led to preparation of the actionability report. )", "condition": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/co", "id": "CG-AC:AC025/co", "type": "GeneticCondition", "label": "PTEN Hamartoma Tumor Syndrome - Cowden Syndrome", "description": "CS is a multiple hamartoma syndrome with a high risk for benign and malignant tumors of the thyroid, breast, and endometrium. Affected individuals usually have macrocephaly, trichilemmomas, and papillomatous papules, and present by the late 20s." }, "outcome": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ou/Thyroid%20cancer", "id": "CG-AC:AC025/ou/Thyroid cancer", "type": "Outcome", "label": "Thyroid cancer" } ], "intervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/intv/Surveillance", "id": "CG-AC:AC025/intv/Surveillance", "type": "Intervention", "label": "Surveillance" } ], "clinicalActionabilityProfile": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/cap", "id": "CG-AC:AC025/cap", "type": "Assertion", "assertionMethod": "The ClinGen AWG developed a standardized protocol to generate evidence-based profiles of clinical actionability of genes and associated disorders in the form of summary reports and semiquantitative metric (SQM) scores.", "releaseDate": "Wed, 09 Feb 2022 00:00:00 -0000", "releaseNum": "1.0.2" }, "evidenceStatements": { "evidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/en/cf", "id": "CG-AC:AC025/en/cf", "type": "EvidenceNarrative", "narrative": "PHTS encompasses a spectrum of clinical phenotypes historically described as distinct entities, though not all current guidelines have incorporated this new terminology. Therefore, this report presents recommendations and evidence as they are available from existing guidelines, which may target a specific clinical phenotype. Given PHTS exhibits variable expressivity and a general lack of genotype/phenotype correlation, it is appropriate to consider the entire PHTS spectrum in the context of a secondary finding in PTEN. PHTS is associated with multiple hamartomas and/or cancerous lesions in various organs and tissues, including the skin, mucous membranes, breast, thyroid, endometrium, and brain. Mucocutanuous lesions are a main feature of PHTS and include facial trichilemmomas, facial papules, acral keratoses, and oral cavity verrucoid or papillomatous papules. Macrocephaly is a common manifestation. Multiple hamartomatous polyps of varying histologic types distributed throughout the colon and other intestines occur, and may range from few to numerous (even hundreds). PHTS is associated with an increased risk of breast, thyroid, gastric, colon cancers. Renal cell carcinoma and malignant melanoma are also associated with PHTS. Though it is not well-defined, women with PHTS may have a risk of endometrial cancer. Additional features of PHTS may include pigmented macules of the glans penis, cerebellar dysplastic gangliocytoma, lipomas, intellectual disability, and vascular anomalies.", "evidenceDomainTag": "Nature of the Threat.Clinical Features", "publication": [ "CG-AC:RF000103", "CG-AC:RF000172", "CG-AC:RF000175", "CG-AC:RF000176", "CG-AC:RF000335", "CG-AC:RF002525", "CG-AC:RF000226" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/en/potgd", "id": "CG-AC:AC025/en/potgd", "type": "EvidenceNarrative", "narrative": "The true prevalence of PTEN hamartoma tumor syndrome (PHTS) is unknown. PHTS includes Cowden syndrome (CS), Bannayan-Riley-Ruvalcaba syndrome (BRRS), Adult Lhermitte-Duclos disease, PTEN-related Proteus syndrome, Proteus-like syndrome, and autism spectrum disorders with macrocephaly. The incidence of PHTS is unknown. However, the incidence of CS has been reported to be 1 in 200,000, although it is likely to be underestimated due to the difficulties associated with making a clinical diagnosis of the disease given the common findings associated with this syndrome and the variable expression of disease.", "evidenceDomainTag": "Nature of the Threat.Prevalence of the Genetic Disorder", "publication": [ "CG-AC:RF000103", "CG-AC:RF000172", "CG-AC:RF000175", "CG-AC:RF000176", "CG-AC:RF000335", "CG-AC:RF002525" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/en/nh", "id": "CG-AC:AC025/en/nh", "type": "EvidenceNarrative", "narrative": "A meta-analysis of patients with CS indicated a mean age of presentation of 38 years, with a range of 3 to 77 years. By the third decade, 99% of affected individuals develop the mucocutaneous lesions, as well as acral and plantar keratoses. The average age for thyroid disease is 32 years. The average age of breast cancer diagnosis is between 38 and 50 years. The median age of epithelial thyroid cancer onset is 37 years, but has been diagnosed before the age of 18 years and as early as 6 years. Elevated risk for endometrial cancer, colorectal cancer, and renal cell carcinoma starts in the late 30s and early 40s. Individuals are more likely to develop bilateral and multifocal cancer in paired organs. Women with PHTS have been reported to have a 2-fold higher cancer risk compared to men. Some PHTS phenotypes present with congenital malformations and severe tissue overgrowth childhood.", "evidenceDomainTag": "Nature of the Threat.Natural History", "publication": [ "CG-AC:RF000103", "CG-AC:RF000172", "CG-AC:RF000176", "CG-AC:RF000335" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/en/ACMI2560", "id": "CG-AC:AC025/en/ACMI2560", "type": "EvidenceNarrative", "narrative": "Autosomal Dominant", "evidenceDomainTag": "Threat Materialization Chances.Modes of Inheritance" } ], "tieredEvidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/NOI2687", "id": "CG-AC:AC025/ten/NOI2687", "type": "TieredEvidenceNarrative", "narrative": "Management of PHTS includes multiple, periodic invasive and non-invasive screening tests and the possible recommendation of prophylactic organ removal for affected women.", "evidenceDomainTag": "Acceptability of Intervention.Natures of Intervention" }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/PGM2629", "id": "CG-AC:AC025/ten/PGM2629", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "Not provided", "narrative": "Information on the prevalence of PTEN mutations was not available.", "evidenceDomainTag": "Threat Materialization Chances.Prevalences of the Genetic Mutation" }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/EN2677", "id": "CG-AC:AC025/ten/EN2677", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "PHTS clinical phenotypes with variable expression and age-related penetrance have been found in individuals within the same family with the same PTEN variant. CS and BRRS are considered to be the same disorder with variable expression and age-related penetrance.", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes", "publication": [ "CG-AC:RF000175", "CG-AC:RF000335" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/ACPE3662", "id": "CG-AC:AC025/ten/ACPE3662", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "It has been estimated that approximately 80-100% of individuals with CS have macrocephaly.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000103" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/ACPE3663", "id": "CG-AC:AC025/ten/ACPE3663", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "The estimated cumulative lifetime risk for melanoma is 6%.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000103" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/ACPE3664", "id": "CG-AC:AC025/ten/ACPE3664", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Colonic polyps are found in up to 95% of CS patients undergoing colonoscopy with hamartomatous as the most common histologic type, occurring in up to 29%. CS is also associated with a 9-16% lifetime risk of colorectal cancer.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000103", "CG-AC:RF000335", "CG-AC:RF000226" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/ACPE3666", "id": "CG-AC:AC025/ten/ACPE3666", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Estimates of the lifetime risk of endometrial cancer ranges from 5-28%. Lifetime risk of renal cell cancer ranges from 15-35%.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000103", "CG-AC:RF000335", "CG-AC:RF000226" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/ACPE3667", "id": "CG-AC:AC025/ten/ACPE3667", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "1", "narrative": "A meta-analysis of 181 patients with CS reported that 53% had thyroid disease, with thyroid pathology including goiter (41%), adenoma (25%), follicular carcinoma (7%), thyroiditis (7%), papillary carcinoma (6%), cancer (unknown type) (3%), medullary carcinoma (1%), and hyperthyroidism (1%). In addition, 54% of patients had mucocutaneous lesions, 39% had gastrointestinal lesions, 31% had breast lesions, and 28% had macrocephaly.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000172" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/ACPE3668", "id": "CG-AC:AC025/ten/ACPE3668", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "The lifetime risk of breast cancer for females with CS has been estimated at 25-50%, though a higher cumulative lifetime risk of 77-85% in individuals with CS or PTEN pathogenic variants has been reported.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000103", "CG-AC:RF000335" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/ACPE3669", "id": "CG-AC:AC025/ten/ACPE3669", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "2", "narrative": "Among individuals meeting the diagnostic criteria for CS, the cumulative lifetime risk of any cancer is 89%.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000103" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/ACPE3660", "id": "CG-AC:AC025/ten/ACPE3660", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "By the third decade, 99% of affected individuals develop the mucocutaneous stigmata", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000103", "CG-AC:RF000172", "CG-AC:RF000335" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/ACPE3665", "id": "CG-AC:AC025/ten/ACPE3665", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "The estimated penetrance of PTEN pathogenic variants is high, at approximately 80%. More than 90% of individuals with CS have some clinical manifestation of the disorder by the late 20s.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000103", "CG-AC:RF000335" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/ACPE3661", "id": "CG-AC:AC025/ten/ACPE3661", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "Not provided", "narrative": "Most of the available evidence on penetrance relates specifically to CS, however it has been suggested that patients with other PHTS diagnoses associated with PTEN pathogenic variants should be assumed to have CS-associated cancer risks.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000103" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/RR2501", "id": "CG-AC:AC025/ten/RR2501", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "Not provided", "narrative": "No information on relative risk was identified.", "evidenceDomainTag": "Threat Materialization Chances.Relative Risks" }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/ten/CDEC2677", "id": "CG-AC:AC025/ten/CDEC2677", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "4", "narrative": "Given the age of development of cancers in PHTS patients, general population screening would not allow for prophylactic measures to be taken. The increased cancer surveillance in this population will allow detection of tumors at the earliest, most treatable stages.", "evidenceDomainTag": "Condition Escape Detection.Chances to Escape Clinical Detection", "publication": [ "CG-AC:RF000335" ] } ], "tieredRecommendations": [ { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACSU3378", "id": "CG-AC:AC025/tr/ACSU3378", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Melanoma surveillance is recommended to begin by age 18 years with annual physical cutaneous examination.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF000103", "CG-AC:RF000226" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACSU3379", "id": "CG-AC:AC025/tr/ACSU3379", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Endometrial cancer screening through endometrial biopsy every 1 to 2 years may be considered. However, there are no data on screening for endometrial cancer in CS patients and thus no proven benefit. Patient education is encouraged regarding the symptoms of endometrial cancer including the necessity of a prompt response to symptoms such as abnormal bleeding. Prompt reporting promotes early detection of endometrial cancer.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF000103" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACSU3377", "id": "CG-AC:AC025/tr/ACSU3377", "type": "TieredRecommendation", "evidenceSourceTier": "1", "recommendation": "Breast cancer surveillance is recommended to start at age 40 with annual mammography. Earlier surveillance, beginning at age 30, may be considered. No direct evidence on the effectiveness of breast cancer surveillance in patients with PHTS or PTEN pathogenic variants was identified. Evidence cited in guidelines was based on patients with a BRCA1/2 pathogenic variant or a family history of breast cancer. One guideline summarizes that low quality evidence suggests a disease-specific survival benefit with mammographic surveillance in women aged less than 50 years with a family history of breast cancer. First, an observational study found that death from breast cancer was less likely in women aged less than 50 years with family history whose breast cancer was diagnosed during mammographic surveillance compared to a control group of unscreened women of similar age who developed breast cancer (lead time adjusted HR=0.24; 95% CI: 0.09-0.66]). Second, a study modelled death from breast cancer in a mammographic surveillance study in women with a family history aged less than 50 years and a control group from another study, using prognostic features at diagnosis and underlying risk. Projected ten-year death from breast cancer was lower in the mammographic surveillance group than in the control group of unscreened women of similar age (RR=0.80; 95% CI: 0.66-0.96). Third, a retrospective study found that death from any cause was less likely in BRCA1/2 mutation carriers aged between 28 and 77 years diagnosed with breast cancer during an intensive mammographic surveillance program than in those diagnosed outside this program (HR=0.44; 95% CI: 0.25-0.77]).", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF000517" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACPM4873", "id": "CG-AC:AC025/tr/ACPM4873", "type": "TieredRecommendation", "evidenceSourceTier": "1", "recommendation": "No direct evidence on the effectiveness of risk-reducing surgery in patients with PHTS or PTEN pathogenic variants was identified. Findings from 2 observational studies and 3 decision analysis studies suggest that risk-reducing subcutaneous/total mastectomy has a beneficial effect in terms of significantly reducing the risk of breast cancer in women with a family history of breast cancer, or with BRCA1/2 pathogenic variants. One of the observational studies found that risk-reducing mastectomy was also associated with a reduction in breast cancer mortality in women with a family history of breast cancer. Among the two observational studies, one found no cases of invasive breast cancer among women who had undergone bilateral total mastectomy over 3 years (compared to 8/63 patients undergoing surveillance only). The second study showed a reduction in the risk of breast cancer of 89.5% in moderate-risk women who had undergone mastectomy and a reduction of 90-94% among high-risk women. The risk reduction for death among women undergoing mastectomy was 100% among moderate-risk women, and 81-94% among high-risk women.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF000517" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACPM4875", "id": "CG-AC:AC025/tr/ACPM4875", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "The option of risk-reducing mastectomy and hysterectomy should be discussed on a case-by-case basis.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF000103" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACPM4872", "id": "CG-AC:AC025/tr/ACPM4872", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Psychomotor assessment should be considered at diagnoses in children, including brain MRI if symptoms are present.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF000103" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACPM4874", "id": "CG-AC:AC025/tr/ACPM4874", "type": "TieredRecommendation", "evidenceSourceTier": "4", "recommendation": "To establish the extent of disease and needs of an individual diagnosed, the following evaluations are recommended: \\n•Complete medical history and family history\\n•Physical examination, paying particular attention to skin, mucous membranes, thyroid, and breasts\\n•In children, consideration of neurodevelopmental evaluation\\n•Urinalysis with cytospin\\n•Consultation with a clinical geneticist and/or genetic counselor.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF000335" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACCA3098", "id": "CG-AC:AC025/tr/ACCA3098", "type": "TieredRecommendation", "evidenceSourceTier": "4", "recommendation": "Because of the propensity for rapid tissue regrowth, it is recommended that cutaneous lesions be excised only if malignancy is suspected or symptoms are significant.", "evidenceDomainTag": "Effectiveness of Intervention.Circumstances to Avoid", "publication": [ "CG-AC:RF000335" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACSU3383", "id": "CG-AC:AC025/tr/ACSU3383", "type": "TieredRecommendation", "evidenceSourceTier": "1", "recommendation": "No data regarding the effectiveness of melanoma surveillance in pathogenic PTEN variant carriers was found. A systematic review addressing visual screening for skin cancer identified no trials addressing the effectiveness of skin cancer screening on morbidity and mortality in average-risk individuals. One ecological study found that after the implementation of a population based skin cancer screening program the population age- and sex-adjusted melanoma mortality decreased by 48% with an absolute mortality difference of 0.8 melanoma deaths per 100,000 persons. Eight observational studies examined the association between lesion thickness or stage at diagnosis and mortality. All studies demonstrated a consistent linear increase in the risk of melanoma mortality with increasing tumor thickness. Tumor thickness >4.0mm was associated with a hazard ratio of 3.1-32.6 in multivariate models, indicating increased risk of melanoma mortality compared with thinner lesions.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF000383" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACSU3385", "id": "CG-AC:AC025/tr/ACSU3385", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Surveillance for renal cell carcinoma utilizing annual urine analysis with cytology and possible renal ultrasound is recommended. Age to start varies across guidelines, from age 18 to 40 years.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF000103", "CG-AC:RF000226" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACSU3384", "id": "CG-AC:AC025/tr/ACSU3384", "type": "TieredRecommendation", "evidenceSourceTier": "1", "recommendation": "No evidence was identified related to effectiveness of colonoscopy and other gastrointestinal surveillance in individuals with PHTS. Evidence based on screening in individuals with Lynch Syndrome (LS) and FAP indicates a decrease in the risk of colorectal cancer (CRC). In a systematic review evaluating both conditions, five out of six studies in patients with LS found a significantly reduced incidence rate of CRC with surveillance (OR estimates ranged from 0.11 to 0.35), while the sixth study reporting an OR of 0.93 was not significant. Two out of four LS studies showed a significant reduction in CRC-related mortality with surveillance (OR estimates range from 0.04 to 0.17), while three of the four LS studies reported no mortality in the study arm with surveillance. Among individuals with FAP, 26 of 27 studies showed a statistically significant reduction in CRC incidence with surveillance (ORs ranged from 0.01 to 0.37) in screened patients compared to those who presented symptomatically with polyposis/CRC outside of a screening program. Eight FAP studies examined CRC mortality, all of which showed a significant reduction in CRC mortality (ORs ranged from <0.01 to 0.16) in screened (N= 1028) versus symptomatic groups (N= 947). Two FAP studies provided evidence for complete prevention of CRC-related deaths during surveillance, although the duration of follow-up was short (2-4 years).", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF000114" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACSU3381", "id": "CG-AC:AC025/tr/ACSU3381", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Patients should undergo colonoscopy and esophagogastroduodenoscopy. The age to begin varies across guidelines, from age 15 to 35. The frequency also varies across guidelines, from every 2 to every 5 years.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF000103", "CG-AC:RF000226" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACSU3382", "id": "CG-AC:AC025/tr/ACSU3382", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "No evidence for effectiveness for thyroid surveillance in PHTS patients was found. A single study comparing familial adenomatous polyposis (FAP) patients with screen-detected thyroid cancer to those with incident thyroid cancers showed that screening led to detection of smaller tumors with fewer positive lymph nodes.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF000818" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACSU3380", "id": "CG-AC:AC025/tr/ACSU3380", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Patients should receive annual thyroid ultrasound and thyroid exam starting at time of diagnosis, including in childhood.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF000103", "CG-AC:RF000226" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/tr/ACSU3386", "id": "CG-AC:AC025/tr/ACSU3386", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Patients should undergo annual comprehensive physical examinations starting at age 18 years or 5 years before the youngest age of diagnosis of a component cancer in the family, whichever comes first. Patients should also be educated regarding the signs and symptoms of cancer.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF000103" ] } ] }, "evidenceCategory": { "outcomeEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/oei", "id": "CG-AC:AC025/oei", "type": "EvidenceItem", "natureOfTheThreat": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/oei/nott", "id": "CG-AC:AC025/oei/nott", "type": "EvidenceLine", "prevalenceOfTheGeneticDisorder": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/oei/pgd", "id": "CG-AC:AC025/oei/pgd", "type": "EvidenceItem", "keyText": "Unknown", "sourceOfPopulation": "Other", "evidenceNarrative": { "@id": "CG-AC:AC025/en/potgd" } }, "clinicalFeatures": { "@id": "https://actionability.clinicalgenome.org/ac/Pediatric/api/sepio/doc/AC025/oei/cf", "id": "CG-AC:AC025/oei/cf", "type": "EvidenceItem", 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