Abstract
BackgroundPathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked BioMe Biobank in New York City.MethodsExome sequence data from 30,223 adult BioMe participants were evaluated for pathogenic variants in BRCA1/2. Prevalence estimates were made in population groups defined by genetic ancestry and self-report. EHR data were used to evaluate clinical characteristics of variant-positive individuals.ResultsThere were 218 (0.7%) individuals harboring expected pathogenic variants, resulting in an overall prevalence of 1 in 139. The highest prevalence was in individuals with Ashkenazi Jewish (AJ; 1 in 49), Filipino and other Southeast Asian (1 in 81), and non-AJ European (1 in 103) ancestry. Among 218 variant-positive individuals, 112 (51.4%) harbored known founder variants: 80 had AJ founder variants (BRCA1 c.5266dupC and c.68_69delAG, and BRCA2 c.5946delT), 8 had a Puerto Rican founder variant (BRCA2 c.3922G>T), and 24 had one of 19 other founder variants. Non-European populations were more likely to harbor BRCA1/2 variants that were not classified in ClinVar or that had uncertain or conflicting evidence for pathogenicity (uncertain/conflicting). Within mixed ancestry populations, such as Hispanic/Latinos with genetic ancestry from Africa, Europe, and the Americas, there was a strong correlation between the proportion of African genetic ancestry and the likelihood of harboring an uncertain/conflicting variant. Approximately 28% of variant-positive individuals had a personal history, and 45% had a personal or family history of BRCA1/2-associated cancers. Approximately 27% of variant-positive individuals had prior clinical genetic testing for BRCA1/2. However, individuals with AJ founder variants were twice as likely to have had a clinical test (39%) than those with other pathogenic variants (20%).ConclusionsThese findings deepen our knowledge about BRCA1/2 variants and associated cancer risk in diverse populations, indicate a gap in knowledge about potential cancer-related variants in non-European populations, and suggest that genomic screening in diverse patient populations may be an effective tool to identify at-risk individuals.
Highlights
Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations
The proportion of individuals harboring BRCA1/2 variants that were not classified in ClinVar was lowest in individuals of self-reported European descent (0.8%) and highest in individuals of South HA Hispanic/Latino (Asian) descent (2.3%; Fig. 1a)
The proportion of individuals harboring BRCA1/2 variants of uncertain significance or with conflicting interpretations of pathogenicity in ClinVar was lowest in individuals of self-reported European descent (4.1%) and highest in those of self-reported African American/African descent (12.2%; Fig. 1b)
Summary
Pathogenic variants in BRCA1 and BRCA2 (BRCA1/2) lead to increased risk of breast, ovarian, and other cancers, but most variant-positive individuals in the general population are unaware of their risk, and little is known about prevalence in non-European populations. The risk for other cancers, including prostate, male breast, pancreas, melanoma and possibly others, is increased [4]. Pathogenic variants in these genes are highly penetrant and inherited in an autosomal dominant pattern. A higher prevalence has been observed in certain populations; for example, approximately 1 in 42 individuals of Ashkenazi Jewish (AJ) descent harbor one of three common founder variants [7, 8]. Recent unselected population-based genomic screening efforts have demonstrated a higher than expected prevalence of BRCA1/ 2 pathogenic variants in predominantly European-ancestry individuals, approximately 1 in 190, with only half of these individuals meeting current guidelines for genetic testing [10,11,12] and only 18% having prior knowledge of their BRCA1/2 status through clinical genetic testing [13]
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