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Importance: Detection of disease-associated variants in the BRCA1 and BRCA2 (BRCA1/2) genes allows for cancer prevention and early diagnosis in high-risk individuals., Objectives: To identify pathogenic and likely pathogenic (P/LP) BRCA1/2 variants in an unselected research cohort, and to characterize the features associated with P/LP variants., Design, Setting, and Participants: 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 BRCA1/2., Main Outcomes: Prevalence of P/LP BRCA1/2 variants in cohort, proportion of variant carriers not previously ascertained through clinical testing, and personal and family history of relevant cancers among BRCA1/2 variant carriers and noncarriers., Results: Of the 50 726 health system patients who underwent exome sequencing, 50 459 (99.5%) had no expected pathogenic BRCA1/2 variants and 267 (0.5%) were BRCA1/2 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 BRCA1/2 variants, 219 (82.0%) had no prior clinical testing, 95 (35.6%) had BRCA1 variants, and 172 (64.4%) had BRCA2 variants. Syndromic cancer diagnoses were present in 11 (47.8%) of the 23 deceased BRCA1/2 carriers and in 56 (20.9%) of all 267 BRCA1/2 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; P < .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; P < .001). Among 89 BRCA1/2 carriers without prior testing but with comprehensive personal and family history data, 44 (49.4%) did not meet published guidelines for clinical testing., Conclusions and Relevance: This study found that compared with previous clinical care, exome sequencing-based screening identified 5 times as many individuals with P/LP BRCA1/2 variants. These findings suggest that genomic screening may identify BRCA1/2-associated cancer risk that might otherwise remain undetected within health care systems and may provide opportunities to reduce morbidity and mortality in patients.

Purpose: Racial disparities in BRCA1/2 testing have been documented, but causes of these disparities are poorly understood. The study objective was to investigate whether the distribution of black and white patients across cancer providers contributes to disparities in BRCA1/2 testing., Patients and Methods: We conducted a population-based study of women in Pennsylvania and Florida who were 18 to 64 years old and diagnosed with invasive breast cancer between 2007 and 2009, linking cancer registry data, the American Medical Association Physician Masterfile, and patient and physician surveys. The study included 3,016 women (69% white, 31% black), 808 medical oncologists, and 732 surgeons., Results: Black women were less likely to undergo BRCA1/2 testing than white women (odds ratio [OR], 0.40; 95% CI, 0.34 to 0.48; P < .001). This difference was attenuated but not eliminated by adjustment for mutation risk, clinical factors, sociodemographic characteristics, and attitudes about testing (OR, 0.66; 95% CI, 0.53 to 0.81; P < .001). The care of black and white women was highly segregated across surgeons and oncologists (index of dissimilarity 64.1 and 61.9, respectively), but adjusting for clustering within physician or physician characteristics did not change the size of the testing disparity. Black women were less likely to report that they had received physician recommendation for BRCA1/2 testing even after adjusting for mutation risk (OR, 0.66; 95% CI, 0.54 to 0.82; P < .001). Adjusting for physician recommendation further attenuated the testing disparity (OR, 0.76; 95% CI, 0.57 to 1.02; P = .06)., Conclusion: Although black and white patients with breast cancer tend to see different surgeons and oncologists, this distribution does not contribute to disparities in BRCA1/2 testing. Instead, residual racial differences in testing after accounting for patient and physician characteristics are largely attributable to differences in physician recommendations. Efforts to address these disparities should focus on ensuring equity in testing recommendations., Competing Interests: Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article., (© 2016 by American Society of Clinical Oncology.)