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Population-Based Penetrance of Deleterious Clinical Variants

Educational Objective
To understand how the population-based disease risk can be determined for clinical variants in known disease-predisposition genes.
1 Credit CME
Key Points

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.

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Article Information

Corresponding Author: Ron Do, PhD, 1468 Madison Ave, Annenberg Building, Floor 18, Room 80B, New York, NY 10029 (ron.do@mssm.edu).

Accepted for Publication: December 13, 2021.

Author Contributions: Dr Do and Mr Forrest had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

Concept and design: Forrest, Jordan, Cho, Do.

Acquisition, analysis, or interpretation of data: All authors.

Drafting of the manuscript: Forrest, Cho, Do.

Critical revision of the manuscript for important intellectual content: All authors.

Statistical analysis: Forrest, Chaudhary, Petrazzini, Rocheleau, Cho.

Obtained funding: Forrest, Loos, Cho, Do.

Administrative, technical, or material support: Vy, Bafna, Cho.

Supervision: Rocheleau, Nadkarni, Cho, Do.

Conflict of Interest Disclosures: Mr Forrest reported receiving grants from the National Institute of General Medical Sciences of the National Institutes of Health (NIH). Dr Nadkarni reported receiving grants, personal fees, and nonfinancial support from and being a cofounder of and having equity in Renalytix; being a cofounder in Pensieve Health; being a cofounder and having equity in Verici; and receiving personal fees from Siemens, Reata, AstraZeneca, and BioVie outside the submitted work. Dr Do reported receiving grants from AstraZeneca and Goldfinch Bio; nonfinancial support from Goldfinch Bio; personal fees from Variant Bio; and being a scientific cofounder, consultant, and equity holder in Pensieve Health outside the submitted work. No other disclosures were reported.

Funding/Support: Mr Forrest is supported by the National Institute of General Medical Sciences of the National Institutes of Health (NIH) (T32-GM007280). Dr Do is supported by the National Institute of General Medical Sciences of the NIH (R35-GM124836) and the National Heart, Lung, and Blood Institute of the NIH (R01-HL139865 and R01-HL155915).

Role of the Funder/Sponsor: The National Institute of General Medical Sciences and the National Heart, Lung, and Blood Institute of the NIH had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; or decision to submit the manuscript for publication; and no right to veto publication of the manuscript.

Disclaimer: The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Additional Contributions: Bruce D. Gelb, MD; Sander Houten, PhD; Paz Polak, PhD; and Stuart Scott, PhD, all of whom are on the thesis advisory committee of Iain Forrest, provided critical feedback and expertise. All contributors are affiliated with the Icahn School of Medicine at Mount Sinai and no one received any additional compensation beyond usual salary for their contributions to this study.

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