{"doi":"10.1001/jama.2021.23686","title":"Population-Based Penetrance of Deleterious Clinical Variants","abstract":"Importance: Population-based assessment of disease risk associated with gene variants informs clinical decisions and risk stratification approaches. Objective: To evaluate the population-based disease risk of clinical variants in known disease predisposition genes. Design, Setting, and Participants: This cohort study included 72 434 individuals with 37 780 clinical variants who were enrolled in the BioMe Biobank from 2007 onwards with follow-up until December 2020 and the UK Biobank from 2006 to 2010 with follow-up until June 2020. Participants had linked exome and electronic health record data, were older than 20 years, and were of diverse ancestral backgrounds. Exposures: Variants previously reported as pathogenic or predicted to cause a loss of protein function by bioinformatic algorithms (pathogenic/loss-of-function variants). Main Outcomes and Measures: The primary outcome was the disease risk associated with clinical variants. The risk difference (RD) between the prevalence of disease in individuals with a variant allele (penetrance) vs in individuals with a normal allele was measured. Results: Among 72 434 study participants, 43 395 were from the UK Biobank (mean [SD] age, 57 [8.0] years; 24 065 [55%] women; 2948 [7%] non-European) and 29 039 were from the BioMe Biobank (mean [SD] age, 56 [16] years; 17 355 [60%] women; 19 663 [68%] non-European). Of 5360 pathogenic/loss-of-function variants, 4795 (89%) were associated with an RD less than or equal to 0.05. Mean penetrance was 6.9% (95% CI, 6.0%-7.8%) for pathogenic variants and 0.85% (95% CI, 0.76%-0.95%) for benign variants reported in ClinVar (difference, 6.0 [95% CI, 5.6-6.4] percentage points), with a median of 0% for both groups due to large numbers of nonpenetrant variants. Penetrance of pathogenic/loss-of-function variants for late-onset diseases was modified by age: mean penetrance was 10.3% (95% CI, 9.0%-11.6%) in individuals 70 years or older and 8.5% (95% CI, 7.9%-9.1%) in individuals 20 years or older (difference, 1.8 [95% CI, 0.40-3.3] percentage points). Penetrance of pathogenic/loss-of-function variants was heterogeneous even in known disease predisposition genes, including BRCA1 (mean [range], 38% [0%-100%]), BRCA2 (mean [range], 38% [0%-100%]), and PALB2 (mean [range], 26% [0%-100%]). Conclusions and Relevance: In 2 large biobank cohorts, the estimated penetrance of pathogenic/loss-of-function variants was variable but generally low. Further research of population-based penetrance is needed to refine variant interpretation and clinical evaluation of individuals with these variant alleles.","journal":"JAMA","year":2022,"id":234105,"datarank":3.6534583198137627,"base_score":4.68213122712422,"endowment":4.68213122712422,"self_citation_contribution":0.7023196840686331,"citation_network_contribution":2.9511386357451297,"self_endowment_contribution":0.7023196840686331,"citer_contribution":2.9511386357451297,"corpus_percentile":null,"corpus_rank":null,"citation_count":107,"citer_count":96,"citers_with_citation_signal":70,"citers_with_endowment":70,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.736,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":483550,"name":"Kumardeep Chaudhary","orcid":"0000-0002-4117-6403","position":1,"is_corresponding":false},{"id":58024,"name":"Ha My T. Vy","orcid":"0000-0002-5117-3740","position":2,"is_corresponding":false},{"id":58027,"name":"Ben Omega Petrazzini","orcid":"0000-0001-9789-9371","position":3,"is_corresponding":false},{"id":786091,"name":"Shantanu Bafna","orcid":"0000-0002-5299-9325","position":4,"is_corresponding":false},{"id":58026,"name":"Daniel M. Jordan","orcid":"0000-0002-5318-8225","position":5,"is_corresponding":false},{"id":58025,"name":"Ghislain Rocheleau","orcid":"0000-0002-9989-7553","position":6,"is_corresponding":false},{"id":1082,"name":"Ruth J. F. Loos","orcid":"0000-0002-8532-5087","position":7,"is_corresponding":false},{"id":5026,"name":"Girish N. Nadkarni","orcid":"0000-0001-6319-4314","position":8,"is_corresponding":false},{"id":105285,"name":"Judy H. Cho","orcid":"0000-0002-7959-0466","position":9,"is_corresponding":false},{"id":23900,"name":"Ron Do","orcid":"0000-0002-3144-3627","position":10,"is_corresponding":false},{"id":58023,"name":"Iain S. Forrest","orcid":"0000-0002-5642-422X","position":0,"is_corresponding":true}],"reference_count":41,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:21:36.529874Z","pmid":"35076666","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}