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Abstract
Background
Unbiased estimates of penetrance are challenging but critically important to make informed choices about strategies for risk management through increased surveillance and risk-reducing interventions.
Methods
We studied the penetrance and clinical outcomes of 7 breast cancer susceptibility genes (BRCA1, BRCA2, TP53, CHEK2, ATM, PALB2, and PTEN) in almost 13 458 participants unselected for personal or family history of breast cancer. We identified 242 female participants with pathogenic or likely pathogenic variants in 1 of the 7 genes for penetrance analyses, and 147 women did not previously know their genetic results.
Results
Out of the 147 women, 32 women were diagnosed with breast cancer at an average age of 52.8 years. Estimated penetrance by age 60 years ranged from 17.8% to 43.8%, depending on the gene. In clinical-impact analysis, 42.3% (95% confidence interval = 31.3% to 53.3%) of women had taken actions related to their genetic results, and 2 new breast cancer cases were identified within the first 12 months after genetic results disclosure.
Conclusions
Our study provides population-based penetrance estimates for the understudied genes CHEK2, ATM, and PALB2 and highlights the importance of using unselected populations for penetrance studies. It also demonstrates the potential clinical impact of genetic testing to improve health care through early diagnosis and preventative screening.
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Details
1 Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA
2 Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA
3 Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA
4 Irving Institute for Clinical and Translational Research, Columbia University Irving Medical Center, New York, NY, USA
5 Genomic Medicine Institute, Geisinger, Danville, PA, USA
6 Department of Medicine, Northwestern University, Chicago Feinberg School of Medicine, Chicago, IL, USA
7 Center for Genetic Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
8 Department of Preventive Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
9 Department of Biomedical Informatics, Vanderbilt University Medical Center, Nashville, TN, USA
10 Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA
11 Division of Genetic Medicine, Department of Internal Medicine, University of Michigan, Ann Arbor, MI, USA
12 Department of Medicine (Medical Genetics), University of Washington Medical Center, Seattle, WA, USA
13 Department of Biomedical Informatics and Medical Education, University of Washington Medical Center, Seattle, WA, USA
14 Kaiser Permanente Washington Health Research Institute, Seattle, WA, USA
15 Division of Genomic Medicine, National Human Genome Research Institute, National Institutes of Health, Baltimore, MD, USA
16 Center for Precision Medicine Research, Marshfield Clinic, Marshfield, WI, USA
17 Department of Systems Biology, Columbia University Irving Medical Center, New York, NY, USA; Department of Biomedical Informatics, Columbia University Irving Medical Center, New York, NY, USA
18 Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA
19 Department of Pediatrics, Columbia University Irving Medical Center, New York, NY, USA; Herbert Irving Comprehensive Cancer Center, Columbia University Irving Medical Center, New York, NY, USA; Department of Medicine, Columbia University Irving Medical Center, New York, NY, USA