Population-Based Penetrance of Deleterious Clinical Variants

• Published in: JAMA : the journal of the American Medical Association 2022-01, Vol.327 (4), p.350-359
• Main Authors: Forrest, Iain S, Chaudhary, Kumardeep, Vy, Ha My T, Petrazzini, Ben O, Bafna, Shantanu, Jordan, Daniel M, Rocheleau, Ghislain, Loos, Ruth J. F, Nadkarni, Girish N, Cho, Judy H, Do, Ron
• Format: Article
• Language: English
• Subjects: Age; Aged; Algorithms; Alleles; Biobanks; Biological Specimen Banks; BRCA1 protein; BRCA2 protein; Breast cancer; Cohort Studies; Disease; Electronic health records; Electronic medical records; Evaluation; Female; Genes; Genetic Predisposition to Disease; Genetic Variation; Health risks; Humans; Loss of Function Mutation; Male; Mutation; Original Investigation; Penetrance; Population; United Kingdom
• ISSN: 0098-7484; 1538-3598
• DOI: 10.1001/jama.2021.23686

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