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

Abul-Husn NS1,2,3,4, Soper ER5,6, Odgis JA5,6, Cullina S5,6, Bobo D5,6, Moscati A5,6, Rodriguez JE5,6; CBIPM Genomics Team; Regeneron Genetics Center, Loos RJF6, Cho JH6,7,8, Belbin GM5,6,7, Suckiel SA5,6, Kenny EE5,6,7,8.

Author information

1: The Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA. noura.abul-husn@mssm.edu.
2: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. noura.abul-husn@mssm.edu.
3: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA. noura.abul-husn@mssm.edu.
4: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA. noura.abul-husn@mssm.edu.
5: The Center for Genomic Health, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
6: The Charles Bronfman Institute for Personalized Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
7: Department of Medicine, Icahn School of Medicine at Mount Sinai, New York, NY, USA.
8: Department of Genetics and Genomic Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA.

Abstract

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 BioMe Biobank in New York City.

METHODS:

Exome 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.

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.