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

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.

Clinical outcomes of a genomic screening program for actionable genetic conditions

“…For example, our group and others have found that screening unselected cohorts for pathogenic/likely pathogenic BRCA1/2 variants can lead to improved ascertainment of individuals with these variants, 50% of whom did not have a personal or family history indicating their increased cancer risk. 1 – 3 Further, genomic screening programs can identify individuals with early-onset cancers 4 and improve medication management in individuals with high cholesterol levels. 5 …”

Genomic Screening Identifies Individuals at High Risk for Hereditary Transthyretin Amyloidosis

“…The Bio Me Biobank is an ongoing electronic health record (EHR)-linked biorepository in New York City. Over 55,000 Bio Me participants have been enrolled since 2007, predominantly through unselected medicine and specialty ambulatory care practices across the Mount Sinai Health System (MSHS) [ 5 , 31 ]. A subset of Bio Me participants have undergone exome sequencing and genotyping through a collaboration with the Regeneron Genetics Center [ 5 ].…”

“…Over 55,000 Bio Me participants have been enrolled since 2007, predominantly through unselected medicine and specialty ambulatory care practices across the Mount Sinai Health System (MSHS) [ 5 , 31 ]. A subset of Bio Me participants have undergone exome sequencing and genotyping through a collaboration with the Regeneron Genetics Center [ 5 ]. In October 2018, the Bio Me protocol and consent were modified to include the option for participants to receive clinically confirmed, medically actionable genomic results.…”

“…Self-reported race/ethnicity groups were derived from a survey administered to participants upon enrollment into Bio Me , as previously described [ 5 , 31 ]. A list of hATTR- related phenotypes was compiled to query participants’ medical records.…”

“…Genomic screening programs, typically performed in the setting of large health system clinics [ 4 ], biobanks [ 2 ], or public health initiatives [ 3 ], may choose to return medically actionable findings with varying degrees of clinical utility. Recent studies have found that most individuals at genomic risk for medically actionable conditions are unaware of their risk [ 5 , 6 , 7 ], and that the majority of individuals informed of such risk will undergo recommended surveillance or risk-reducing interventions [ 2 , 8 ]. Therefore, genomic screening holds the promise of identifying preventable and treatable diseases that may be otherwise missed in routine clinical care.…”