Abstract
Detection of disease-associated variants in the BRCA1 and BRCA2 (BRCA1/2) genes allows for cancer prevention and early diagnosis in high-risk individuals. 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. 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. 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. 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. 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.
Highlights
Pathogenic variants in the BRCA1 (OMIM 113705) and BRCA2 (OMIM 600185) genes were first associated with familial breast cancer risk in the mid-1990s.1,2 Associated risks for ovarian cancer, prostate cancer, pancreatic cancer, and melanoma have since been documented; these clinical associations are grouped as hereditary breast and ovarian cancer (HBOC) syndrome.[3]Clinical testing for pathogenic variants in the BRCA1 and BRCA2 gene became available in 1995.4 Risk-assessment strategies, based on personal and family history cancer thresholds, have been built, validated, and incorporated into clinical testing guidelines
31 (20.9%) of 148 variant carriers had a personal history of breast cancer, compared with 1554 (5.2%) of 29 880 noncarriers
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)
Summary
Clinical testing for pathogenic variants in the BRCA1 and BRCA2 (ie, BRCA1/2) gene became available in 1995.4 Risk-assessment strategies, based on personal and family history cancer thresholds, have been built, validated, and incorporated into clinical testing guidelines. These guidelines are routinely used to identify individuals with increased pretest probability of pathogenic BRCA1/2 variants.[5,6] Current established guidelines have been issued by the National Comprehensive Cancer Network (NCCN),[7] the US Preventive Services Task Force,[8] and the American College of Medical Genetics and Genomics together with the National Society of Genetic Counselors.[9]. Clinical underascertainment of individuals with pathogenic BRCA1/2 variants may be associated with the failure to apply testing guideline criteria and the failure of criteria-based strategies to identify all true positives.[10,11] Such underascertainment has been documented even in women with existing cancer diagnoses[12,13] and has prompted calls for DNA sequence–based population screening.[14]
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