{ "@context": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/context/doc", "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108", "id": "CG-AC:AC108", "type": "ClinicalActionabilityReport", "metadata": { "schemaLabel": "AC-Sepio.Beta-1 (Unofficial)", "contentVersionId": "30650", "producedAtUTC": "Thu, 10 Sep 2026 20:41:36 -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/Adult/api/sepio/doc/AC108/co", "id": "CG-AC:AC108/co", "type": "GeneticCondition", "label": "PALB2-related cancers" }, "outcome": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/ou/Breast%20cancer", "id": "CG-AC:AC108/ou/Breast cancer", "type": "Outcome", "label": "Breast cancer" } ], "intervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/intv/Chemoprevention", "id": "CG-AC:AC108/intv/Chemoprevention", "type": "Intervention", "label": "Chemoprevention" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/intv/Mastectomy", "id": "CG-AC:AC108/intv/Mastectomy", "type": "Intervention", "label": "Mastectomy" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/intv/Breast%20cancer%20surveillance", "id": "CG-AC:AC108/intv/Breast cancer surveillance", "type": "Intervention", "label": "Breast cancer surveillance" } ], "clinicalActionabilityProfile": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/cap", "id": "CG-AC:AC108/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": "Fri, 19 Sep 2025 00:00:00 -0000", "releaseNum": "2.3.0", "media": "call" }, "evidenceStatements": { "evidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/en/nh", "id": "CG-AC:AC108/en/nh", "type": "EvidenceNarrative", "narrative": "For PALB2 heterozygotes, breast cancer risk increases with age in women with a pathogenic variant, with a 14% cumulative risk of cancer by age 50 and 35% by age 70. A prospective cohort analysis among heterozygotes of two founder mutations in Poland reported that women with a PALB2 pathogenic variant were diagnosed at a similar age to non-carriers (53.3 vs 53.5); however, PALB2 mutation carriers were found to be at an increased risk of breast cancer (OR=4.39, 95% CI: 2.30-8.37). In addition, patients with PALB2 pathogenic variants were more likely have triple-negative cancers (34% vs. 14%, p<0.0001) and bilateral cancer (10% vs. 3%, p=0.001). The 10-year survival was found to be worse for women with breast cancer and a PALB2 pathogenic variant at 48.0% (95% CI: 36.5–63.2), compared with 74.7% (95% CI: 73.5–75.8) for patients with breast cancer without a pathogenic variant (adjusted hazard ratio for death 2.27, 95% CI: 1.64–3.15; p<0.0001).The risk of breast cancer also increases with family history, with 33% breast cancer risk by age 70 for those with no affected first degree relatives compared to 58% in those with two affected first-degree relatives.", "evidenceDomainTag": "Nature of the Threat.Natural History", "publication": [ "CG-AC:RF000516", "CG-AC:RF000630", "CG-AC:RF000509" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/en/cf", "id": "CG-AC:AC108/en/cf", "type": "EvidenceNarrative", "narrative": "PALB2 interacts with the BRCA2 protein and is involved in DNA repair and tumor suppression. PALB2 pathogenic variants are associated with an increased risk of breast cancer.", "evidenceDomainTag": "Nature of the Threat.Clinical Features", "publication": [ "CG-AC:RF000509" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/en/potgd", "id": "CG-AC:AC108/en/potgd", "type": "EvidenceNarrative", "narrative": "For women, lifetime risk estimates indicate that 12.3% will develop breast cancer and 2.8% will die from it. PALB2 pathogenic variants have been detected in 1-3% of breast cancer cases.", "evidenceDomainTag": "Nature of the Threat.Prevalence of the Genetic Disorder", "publication": [ "CG-AC:RF000511", "CG-AC:RF000630", "CG-AC:RF000509" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/en/ACMI2870", "id": "CG-AC:AC108/en/ACMI2870", "type": "EvidenceNarrative", "narrative": "Autosomal Dominant", "evidenceDomainTag": "Threat Materialization Chances.Modes of Inheritance" } ], "tieredEvidenceNarratives": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/ten/CDEC3146", "id": "CG-AC:AC108/ten/CDEC3146", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "Not provided", "narrative": "Given that women with PALB2 pathogenic variants have an increased risk of breast cancer at younger ages than the general population it is possible that cases could be missed by current screening programs.", "evidenceDomainTag": "Condition Escape Detection.Chances to Escape Clinical Detection" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/ten/NOI3065", "id": "CG-AC:AC108/ten/NOI3065", "type": "TieredEvidenceNarrative", "narrative": "The interventions identified in this report include screening tests, prophylactic surgery to remove target organs, and medications with potential side effects.", "evidenceDomainTag": "Acceptability of Intervention.Natures of Intervention", "publication": [ "CG-AC:RF000517" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/ten/EN3168", "id": "CG-AC:AC108/ten/EN3168", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "Not provided", "evidenceDomainTag": "Threat Materialization Chances.Expressivity Notes" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/ten/PGM3079", "id": "CG-AC:AC108/ten/PGM3079", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "Not provided", "narrative": "Information on PALB2 mutations in the general population was not identified.", "evidenceDomainTag": "Threat Materialization Chances.Prevalences of the Genetic Mutation" }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/ten/RR2798", "id": "CG-AC:AC108/ten/RR2798", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "The breast cancer risk among females who have a germline pathogenic variant in PALB2 is estimated to increase by 2.3 to as high as 9-fold depending on the population, with a pooled risk estimate of 5.3 (90% CI: 3.0-9.4). Relative risk increases when restricted to those at younger ages, with a relative risk 8-9 times higher in those younger than 40, 6-8 times higher in those 40-60, 5 times higher among those older than 60.", "evidenceDomainTag": "Threat Materialization Chances.Relative Risks", "publication": [ "CG-AC:RF000630", "CG-AC:RF000509" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/ten/ACPE4676", "id": "CG-AC:AC108/ten/ACPE4676", "type": "TieredEvidenceNarrative", "evidenceSourceTier": "3", "narrative": "Breast cancer risk increases with age in women with PALB2 pathogenic variants, with a 14% cumulative risk by age 50 and a 35% cumulative risk by age 70.", "evidenceDomainTag": "Threat Materialization Chances.Penetrances", "publication": [ "CG-AC:RF000630", "CG-AC:RF000509" ] } ], "tieredRecommendations": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/tr/ACPM6988", "id": "CG-AC:AC108/tr/ACPM6988", "type": "TieredRecommendation", "evidenceSourceTier": "1", "recommendation": "No direct evidence on the effectiveness of risk-reducing surgery in patients with PALB2 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 and BRCA2 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/Adult/api/sepio/doc/AC108/tr/ACPM6989", "id": "CG-AC:AC108/tr/ACPM6989", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Women with a PALB2 pathogenic variant could consider risk-reducing mastectomy based on their family history.", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF000630" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/tr/ACPM6987", "id": "CG-AC:AC108/tr/ACPM6987", "type": "TieredRecommendation", "evidenceSourceTier": "1", "recommendation": "While no chemoprevention recommendations were identified for patients with PALB2 pathogenic variants specifically, guidelines based on lifetime risk levels similar to those associated with PALB2 pathogenic variants state that healthcare professionals within a specialist genetics clinic should discuss and give written information on the absolute risks and benefits of all options for chemoprevention to women at high risk or moderate risk of breast cancer. No direct evidence on the effectiveness of chemoprevention in patients with PALB2 pathogenic variants was detected. Evidence cited in guidelines was based on patients defined as high-risk based on a family history of breast, ovarian or related (prostate/pancreatic cancer) or with a BRCA1, BRCA2, and/or TP53 pathogenic variant. Among these patients:\\n- High quality evidence from two randomized trials suggests the incidence of breast cancer is lower in patients given tamoxifen than in those given a placebo (RR=0.65; 95% CI: 0.56-0.74). Longer term follow-up from one of these trials has subsequently been published; this study found that over a median of 16 years, there was a significant reduction in the occurrence of all breast cancers in the tamoxifen group (HR=0.71; 95% CI: 0.60 to 0.83; p<0.0001). However, no significant difference was found in breast-cancer specific mortality (OR=1.19; 95% CI: 0.68-2.10; p=0.8). \\n- Low quality evidence from a single randomized trial suggests the incidence of breast cancer is lower in patients given exemestane compared with those given a placebo (HR=0.35; 95% CI: 0.18-0.70)", "evidenceDomainTag": "Effectiveness of Intervention.Patient Managements", "publication": [ "CG-AC:RF000517" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/tr/ACSU4123", "id": "CG-AC:AC108/tr/ACSU4123", "type": "TieredRecommendation", "evidenceSourceTier": "1", "recommendation": "No direct evidence on the effectiveness of breast cancer surveillance in patients with PALB2 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 modeled 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/Adult/api/sepio/doc/AC108/tr/ACSU4124", "id": "CG-AC:AC108/tr/ACSU4124", "type": "TieredRecommendation", "evidenceSourceTier": "2", "recommendation": "Heterozygous female carriers of a PALB2 pathogenic variant are advised to undergo screening with annual mammography starting at age 30, the age when the average 5-year risk for breast cancer exceeds 1%, and may consider screening with breast MRI.", "evidenceDomainTag": "Effectiveness of Intervention.Surveillances", "publication": [ "CG-AC:RF000630" ] } ] }, "evidenceCategory": { "outcomeEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/oei", "id": "CG-AC:AC108/oei", "type": "EvidenceItem", "natureOfTheThreat": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/oei/nott", "id": "CG-AC:AC108/oei/nott", "type": "EvidenceLine", "prevalenceOfTheGeneticDisorder": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/oei/pgd", "id": "CG-AC:AC108/oei/pgd", "type": "EvidenceItem", "keyText": "1-2 in 500", "sourceOfPopulation": "General population", "evidenceNarrative": { "@id": "CG-AC:AC108/en/potgd" } }, "clinicalFeatures": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/oei/cf", "id": "CG-AC:AC108/oei/cf", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC108/en/cf" } }, "naturalHistory": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/oei/nh", "id": "CG-AC:AC108/oei/nh", "type": "EvidenceItem", "evidenceNarrative": { "@id": "CG-AC:AC108/en/nh" } } }, "threatMaterializationChances": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/oei/tmc", "id": "CG-AC:AC108/oei/tmc", "type": "EvidenceLine", "modeOfInheritance": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/oei/moi", "id": "CG-AC:AC108/oei/moi", "type": "EvidenceItem", "keyText": "Autosomal Dominant", "evidenceNarrative": { "@id": "CG-AC:AC108/en/ACMI2870" } }, "prevalenceOfTheGeneticMutation": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/oei/pgm", "id": "CG-AC:AC108/oei/pgm", "type": "EvidenceItem", "keyText": "Unknown", "sourceOfPopulation": "Other", "tieredEvidenceNarrative": { "@id": "CG-AC:AC108/ten/PGM3079" } }, "penetrance": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/oei/pe/ACPE4676", "id": "CG-AC:AC108/oei/pe/ACPE4676", "type": "EvidenceItem", "keyText": "5-39 %", "tieredEvidenceNarrative": { "@id": "CG-AC:AC108/ten/ACPE4676" } } ], "relativeRisk": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/oei/rr/RR2798", "id": "CG-AC:AC108/oei/rr/RR2798", "type": "EvidenceItem", "keyText": ">3", "tieredEvidenceNarrative": { "@id": "CG-AC:AC108/ten/RR2798" } } ], "expressivity": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/oei/ex/EN3168", "id": "CG-AC:AC108/oei/ex/EN3168", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC108/ten/EN3168" } } ] } }, "interventionEvidenceItem": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/iei", "id": "CG-AC:AC108/iei", "type": "EvidenceItem", "acceptabilityOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/iei/aoi", "id": "CG-AC:AC108/iei/aoi", "type": "EvidenceLine", "natureOfIntervention": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/iei/noi/NOI3065", "id": "CG-AC:AC108/iei/noi/NOI3065", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC108/ten/NOI3065" } } ] }, "effectivenessOfIntervention": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/iei/eoi", "id": "CG-AC:AC108/iei/eoi", "type": "EvidenceLine", "patientManagement": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/iei/pm/ACPM6987", "id": "CG-AC:AC108/iei/pm/ACPM6987", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC108/tr/ACPM6987" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/iei/pm/ACPM6989", "id": "CG-AC:AC108/iei/pm/ACPM6989", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC108/tr/ACPM6989" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/iei/pm/ACPM6988", "id": "CG-AC:AC108/iei/pm/ACPM6988", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC108/tr/ACPM6988" } } ], "surveillance": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/iei/su/ACSU4124", "id": "CG-AC:AC108/iei/su/ACSU4124", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC108/tr/ACSU4124" } }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/iei/su/ACSU4123", "id": "CG-AC:AC108/iei/su/ACSU4123", "type": "EvidenceItem", "tieredRecommendation": { "@id": "CG-AC:AC108/tr/ACSU4123" } } ] }, "conditionEscapeDetection": { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/iei/ced", "id": "CG-AC:AC108/iei/ced", "type": "EvidenceLine", "chanceToEscapeDetection": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/AC108/iei/cted/CDEC3146", "id": "CG-AC:AC108/iei/cted/CDEC3146", "type": "EvidenceItem", "tieredEvidenceNarrative": { "@id": "CG-AC:AC108/ten/CDEC3146" } } ] } } }, "references": [ { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF000509", "id": "CG-AC:RF000509", "type": "Publication", "publicationType": "OMIM", "citation": "Online Medelian Inheritance in Man, OMIM. 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Lancet Oncol. (2015) 16(6):638-44.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=25959805", "xdbref": [ "PMID:25959805" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF000517", "id": "CG-AC:RF000517", "type": "Publication", "publicationType": "PMID", "citation": "2013 Jun.", "webUrl": "https://www.ncbi.nlm.nih.gov/pubmed/?term=25340237", "xdbref": [ "PMID:25340237" ] }, { "@id": "https://actionability.clinicalgenome.org/ac/Adult/api/sepio/doc/RF000630", "id": "CG-AC:RF000630", "type": "Publication", "publicationType": "Other", "citation": "true. Genetic/familial high-risk assessment: breast and ovarian (version 2.2017). Publisher: National comprehensive cancer network. (2016) ", "webUrl": "http://www.nccn.org/professionals/physician_gls/pdf/genetics_screening.pdf" } ] }