Exome Sequencing–Based Screening for <i>BRCA1/2</i> Expected Pathogenic Variants Among Adult Biobank Participants
Authors: Kandamurugu Manickam, Adam H. Buchanan, Marci L. B. Schwartz, Miranda L. G. Hallquist, Janet L. Williams, Alanna Kulchak Rahm, Heather Rocha, Juliann M. Savatt, Alyson E. Evans, Loren M. Butry, Amanda L. Lazzeri, D’Andra M. Lindbuchler, Carroll N. Flansburg, Rosemary Leeming, Victor G. Vogel, Matthew S. Lebo, Heather M. Mason-Suares, Derick C. Hoskinson, Noura S. Abul-Husn, Frederick E. Dewey, John D. Overton, Jeffrey G. Reid, Aris Baras, Huntington F. Willard, Cara Z. McCormick, Sarath B. Krishnamurthy, Dustin N. Hartzel, Korey A. Kost, Daniel R. Lavage, Amy C. Sturm, Lauren R. Frisbie, T. Nate Person, Raghu P. Metpally, Monica A. Giovanni, Lacy E. Lowry, Joseph B. Leader, Marylyn D. Ritchie, David J. Carey, Anne E. Justice, H. Lester Kirchner, W. Andrew Faucett, Marc S. Williams, David H. Ledbetter, Michael F. Murray
Journal: JAMA Network Open (2018)

<h3>Importance</h3> Detection of disease-associated variants in the<i>BRCA1</i>and<i>BRCA2</i>(<i>BRCA1/2</i>) genes allows for cancer prevention and early diagnosis in high-risk individuals. <h3>Objectives</h3> To identify pathogenic and likely pathogenic (P/LP)<i>BRCA1/2</i>variants in an unselected research cohort, and to characterize the features associated with P/LP variants. <h3>Design, Setting, and Participants</h3> This is a cross-sectional study of adult volunteers (n = 50 726) who underwent exome sequencing at a single health care system (Geisinger Health System, Danville, Pennsylvania) from January 1, 2014, to March 1, 2016. Participants are part of the DiscovEHR cohort and were identified through the Geisinger MyCode Community Health Initiative. They consented to a research protocol that included sequencing and return of actionable test results. Clinical data from electronic health records and clinical visits were correlated with variants. Comparisons were made between those with (cases) and those without (controls) P/LP variants in<i>BRCA1/2</i>. <h3>Main Outcomes</h3> Prevalence of P/LP<i>BRCA1/2</i>variants in cohort, proportion of variant carriers not previously ascertained through clinical testing, and personal and family history of relevant cancers among<i>BRCA1/2</i>variant carriers and noncarriers. <h3>Results</h3> Of the 50 726 health system patients who underwent exome sequencing, 50 459 (99.5%) had no expected pathogenic<i>BRCA1/2</i>variants and 267 (0.5%) were<i>BRCA1/2</i>carriers. Of the 267 cases (148 [55.4%] were women and 119 [44.6%] were men with a mean [range] age of 58.9 [23-90] years), 183 (68.5%) received clinically confirmed results in their electronic health record. Among the 267 participants with P/LP<i>BRCA1/2</i>variants, 219 (82.0%) had no prior clinical testing, 95 (35.6%) had<i>BRCA1</i>variants, and 172 (64.4%) had<i>BRCA2</i>variants. Syndromic cancer diagnoses were present in 11 (47.8%) of the 23 deceased<i>BRCA1/2</i>carriers and in 56 (20.9%) of all 267<i>BRCA1/2</i>carriers. Among women, 31 (20.9%) of 148 variant carriers had a personal history of breast cancer, compared with 1554 (5.2%) of 29 880 noncarriers (odds ratio [OR], 5.95; 95% CI, 3.88-9.13;<i>P</i> &lt; .001). Ovarian cancer history was present in 15 (10.1%) of 148 variant carriers and in 195 (0.6%) of 29 880 variant noncarriers (OR, 18.30; 95% CI, 10.48-31.4;<i>P</i> &lt; .001). Among 89<i>BRCA1/2</i>carriers without prior testing but with comprehensive personal and family history data, 44 (49.4%) did not meet published guidelines for clinical testing. <h3>Conclusions and Relevance</h3> This study found that compared with previous clinical care, exome sequencing–based screening identified 5 times as many individuals with P/LP<i>BRCA1/2</i>variants. These findings suggest that genomic screening may identify<i>BRCA1/2</i>-associated cancer risk that might otherwise remain undetected within health care systems and may provide opportunities to reduce morbidity and mortality in patients.