Expanding BRCA1/BRCA2 genomic diversity in the Caribbean: insights from the first national cohort in the Dominican Republic

Technical Summary: Expanding BRCA1/BRCA2 Genomic Diversity in the Caribbean

Problem Statement
Despite the global expansion of hereditary cancer testing, Caribbean populations remain significantly underrepresented in BRCA1/BRCA2 reference datasets. This Eurocentric bias in public variant databases (e.g., ClinVar) leads to an over-classification of variants as Variants of Uncertain Significance (VUS) in underrepresented groups, hindering accurate risk assessment, genetic counseling, and the equitable implementation of precision medicine. Specifically, the Dominican Republic, with its unique tri-hybrid genomic ancestry (Indigenous Taíno, Iberian European, and West/Central African), lacks a large-scale characterization of its germline BRCA variant spectrum. Existing literature often fails to distinguish Caribbean populations from African-American or Latin American mestizo cohorts, despite their distinct demographic histories.

Methodology
This study presents a retrospective analysis of a clinically referred cohort from the Dominican Republic.

• Cohort: 648 individuals (after excluding one non-resident) who underwent clinical BRCA1/BRCA2 testing between 2022 and 2025 at Referencia Laboratorio Clínico in Santo Domingo.
• Sequencing: Two complementary Next-Generation Sequencing (NGS) platforms were utilized: the Illumina AmpliSeq™ BRCA Panel on a MiSeq sequencer and the Thermo Fisher Genexus™ Integrated Sequencer with the Oncomine™ BRCA Assay GX.
• Analysis: Variants were standardized using HGVS nomenclature (reference sequences NM_007294.4 and NM_000059.4) and classified according to ACMG/AMP guidelines.
• Comparative Context: The 15 identified pathogenic variants were cross-referenced against curated datasets of African-ancestry individuals and published cohorts from Latin American countries (Mexico, Brazil, Colombia, Peru, Argentina, Chile) to evaluate overlap and potential founder effects.

Key Results

• Positivity Rate: Pathogenic or likely pathogenic BRCA variants were identified in 27 individuals, yielding a positivity rate of 4.2% (95% CI, 2.9–6.0%).
• Variant Spectrum: A total of 15 distinct pathogenic variants were identified: 8 in BRCA1 (40.7% of carriers) and 7 in BRCA2 (59.3% of carriers).
• Variant Types: The spectrum included frameshift deletions/insertions, stop-gain (nonsense) variants, a missense substitution, and a canonical splice-site variant.
• Recurrent Variants: The most frequent variant was BRCA2 c.6486_6489del (p.Lys2162fs), found in 7 carriers (25.9% of the positive cohort). However, this variant has been reported globally (Europe, North America, Asia, Latin America, and Africa), preventing the confirmation of a specific Dominican founder effect based on current data.
• Geographic Distribution: Carriers were distributed across the country, with 51.9% residing in Santo Domingo province, reflecting the clinical referral base rather than a distinct spatial clustering.
• VUS Burden: 55 individuals (8.5%) carried a VUS as their sole finding. Notably, 5 of the 27 pathogenic carriers (18.5%) also carried a concurrent VUS. The most common VUS was BRCA2 c.9976A>T (K3326X), a low-penetrance truncating variant.
• Comparative Findings:
  • Latin America: There was partial overlap with neighboring countries (e.g., BRCA1 c.4327C>T shared with Mexico; BRCA2 c.2808_2811del shared with Brazil, Colombia, Peru). However, the Dominican spectrum did not mirror the high-frequency alleles typically defining "Hispanic/Latino" cohorts in broader meta-analyses.
  • African Ancestry: 8 of the 15 pathogenic variants (53%) had prior reports in self-reported African-ancestry (SRAA) cohorts. However, granular analysis indicated that only BRCA1 c.815_824dup met the criteria for "possibly African" origin; the others were broadly distributed across non-African populations.

Significance and Claims
The authors claim this study provides the first national reference dataset for BRCA1/BRCA2 pathogenic variants in the Dominican Republic and the Caribbean region. The significance of the work is framed as follows:

1. Genomic Representation: It addresses the scarcity of data for Afro-Caribbean populations, which have historically been excluded from hereditary cancer genomics studies due to a lack of qualifying data.
2. Clinical Utility: The catalog of 15 variants supports improved variant interpretation and reduces the reliance on uncertain classifications for Dominican patients. It facilitates more accurate genetic counseling and cascade testing for at-risk relatives.
3. Precision Oncology: By clarifying the pathogenic status of specific variants, the study enables better identification of patients eligible for PARP inhibitors and platinum-based chemotherapy.
4. Foundational Data: The authors explicitly state that while a founder effect for BRCA2 c.6486_6489del cannot be confirmed without haplotype analysis, this dataset serves as the necessary baseline for future population-genomic studies and the eventual confirmation of founder mutations in the region.

The paper maintains a modest tone, acknowledging limitations such as the referral-based nature of the cohort (precluding population-level prevalence estimates), the small number of pathogenic carriers (n=27), and the lack of direct ancestry-informative markers or haplotype analysis in the current study. The authors position this work as a critical first step toward equitable precision medicine in the Caribbean, rather than a definitive conclusion on the region's entire genomic landscape.