Population-Based Penetrance of Deleterious Clinical Variants

Question  What is the population-based penetrance of pathogenic and loss-of-function clinical variants?

Findings  This cohort study included 72 434 participants from 2 biobanks who had alleles for pathogenic or loss-of-function variants reported for 157 diseases. Among the 5360 pathogenic/loss-of-function variants, 4795 (89%) were associated with less than or equal to 5% risk difference for disease in individuals with the variant allele; pathogenic variants were associated with 6.9% mean penetrance and benign variants were associated with 0.85% mean penetrance.

Meaning  In these biobanks, the estimated penetrance of pathogenic/loss-of-function variants varied, but was generally associated with a small increase in the risk of disease.

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.