Journal Article

Exome sequencing reveals a high prevalence of BRCA1 and BRCA2 founder variants in a diverse population-based biobank

Loos, Ruth J. F., Odgis, Jacqueline A., Bobo, Dean, Moscati, Arden, Soper, Emily R., Cullina, Sinead, Kenny, Eimear E., Rodriguez, Jessica E., Cho, Judy H., Abul-Husn, Noura S., Belbin, Gillian M., Suckiel, Sabrina A.

2019

Overview

Background 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. We investigated BRCA1/2 prevalence and impact in the electronic health record (EHR)-linked Bio Me Biobank in New York City. Methods Exome sequence data from 30,223 adult Bio Me 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. Results There 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%). Conclusions These 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.

• Publisher: BioMed Central,Springer Nature B.V,BMC
• Subject: Adult / Aged / Ambulatory care / Biobanks / Bioinformatics / Biological Specimen Banks / Biomedical and Life Sciences / Biomedicine / BRCA1 protein / BRCA1 Protein - genetics / BRCA2 protein / BRCA2 Protein - genetics / Breast / Breast cancer / Cancer Research / Clinical interpretation of genome variation / Ecosystems / Electronic medical records / Exome Sequencing / Family medical history / Female / Genes / Genetic counseling / Genetic screening / Genetic Variation / Genotype / Genotype & phenotype / Heterozygote / Hispanic Americans / Human Genetics / Humans / Male / Medicine/Public Health / Metabolomics / Middle Aged / Native North Americans / Neoplasms - epidemiology / Neoplasms - ethnology / Neoplasms - genetics / Neoplasms - pathology / Ovarian cancer / Pathogenicity / Population genetics / Prevalence / Quality control / Software / Systems Biology