A common pathogenic founder variant in Rwandan breast cancer cases
Germline data from African populations remain sparse, limiting characterization of population-specific BRCA1/2 pathogenic variants (PV). In a study of 175 Rwandan women with breast cancer, 7 unrelated carriers (4% of cases; 22% of PV carriers) harbored the same BRCA1 frameshift PVs, c.4065_4068del (p.Asn1355Lysfs*10), which is extremely rare in gnomAD yet recurrent in European, Asian, and Middle Eastern cohorts. Whole-exome sequencing and haplotype analysis of all 7 carriers revealed a shared ancestral block of approximately 581 kb surrounding the variant, and extended haplotype homozygosity and network analyses confirmed a common founder origin. Coalescent-based age estimation placed the founder event approximately 4,000--10,000 years ago. Comparison with 1000 Genomes Project data showed the founder haplotype is absent or exceedingly rare outside African and South Asian populations. These findings strongly suggest the c.4065_4068del variant as a pre-historical BRCA1 founder variant in Rwanda, with implications for targeted genetic testing, cascade screening, and cancer prevention in the region.
Authors
- Shakuntala Baichoo (ORCID: https://orcid.org/0000-0002-9335-1939)
- Annette Uwineza (ORCID: https://orcid.org/0000-0003-1749-0395)
- Raissa Muvunyi (ORCID: https://orcid.org/0000-0002-2324-3254)
- Eulade Rugengamanzi (ORCID: https://orcid.org/0000-0003-0385-3706)
- Caroline V. Andrews (ORCID: https://orcid.org/0000-0001-5818-4365)
- Sarah M. Nielsen (ORCID: https://orcid.org/0000-0002-5916-6393)
- Temidayo A. Fadelu (ORCID: https://orcid.org/0000-0002-1323-4119)
- Léon Mutesa (ORCID: https://orcid.org/0000-0002-5308-3706)
- Damas Dukundane
- Brianna A. Bucknor (ORCID: https://orcid.org/0009-0001-7200-4655)
- Timothy Richard Rebbeck (ORCID: https://orcid.org/0000-0002-4799-1900)
- Diane Renee Koeller (ORCID: https://orcid.org/0000-0003-1217-9514)
- Jeffrey Besada
- Janvière Mutamuliza (ORCID: https://orcid.org/0009-0008-7388-3277)
- Achille Van Christ Manirakiza (ORCID: https://orcid.org/0000-0002-3829-2016)
- Allison Niragira
Institutions
- University Health Network (CA)
- Harvard University (US)
- LabCorp (United States) (US)
- University of Rwanda (RW)
- Exact Sciences (United States) (US)
- Dana-Farber Cancer Institute (US)
- Rwanda Military Hospital (RW)
- University of Global Health Equity (RW)
- Rwanda Biomedical Center (RW)
- Butaro Hospital (RW)
- Africa Health Sciences University (RW)
- King Faisal Hospital Rwanda (RW)
Publication Details
- Journal
- PLoS Genetics
- Published
- 2026-11-02
- DOI
- https://doi.org/10.1371/journal.pgen.1012180
- Primary Topic
- BRCA gene mutations in cancer
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- U.S. Department of Defense