A common pathogenic founder variant in Rwandan breast cancer cases
Achille V. C. Manirakiza, Shakuntala Baichoo, Annette Uwineza, Damas Dukundane, Eulade Rugengamanzi, Janviere Mutamuliza, Allison M. O. Niragira, Raissa Muvunyi, Jeffrey Besada, Sarah M. Nielsen, Brianna Bucknor, Diane R. Koeller, Caroline Andrews, Leon Mutesa, Temidayo Fadelu, Timothy R. RebbeckGermline 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.