{ "abstract": "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. Author summary: Breast cancer is rising rapidly across sub-Saharan Africa, yet little is known about inherited gene variants that drive hereditary risk in African women. We investigated a recurring mutation in the BRCA1 gene, whose normal function protects against breast and ovarian cancer. We observed this mutation at unexpectedly high frequency among Rwandan women with breast cancer. We found that 7 of 175 women tested (4%) carried the exact same BRCA1 mutation, called c.4065_4068del, despite none being known relatives. To determine whether this recurrence reflected a shared ancestor, we analyzed the DNA surrounding the mutation in all 7 women. All 7 carried a nearly identical DNA stretch around the mutation, a hallmark of what geneticists call a “founder effect,” where a mutation present in one common ancestor spreads to many descendants over generations. Formal relatedness testing confirmed the women are not closely related, meaning this shared mutation traces back thousands of years to a common prehistoric ancestor. All 7 carriers had triple-negative breast cancer, one of the most aggressive subtypes, and most presented with advanced disease. These findings have direct implications for genetic counseling, population-level testing, and cancer prevention in Rwanda and neighboring East African countries.", "abstract_shown": true, "affiliations": [ "Oncology Service, Department of Medicine, King Faisal Hospital Rwanda, Kigali, Rwanda", "Africa Health Sciences University, Kigali, Rwanda", "Center for Human Genetics and Genomics, School of Medicine and Pharmacy, College of Medicine and Health Sciences, University of Rwanda, Kigali, Rwanda", "PMCC-AI, University Health Network, Toronto, Canada", "Dana Farber Cancer Institute, Boston, Massachusetts, United States of America", "Oncology department, Butaro Level II Teaching Hospital, Butaro, Rwanda", "Medical Department, University of Global Health Equity (UGHE), Butaro, Rwanda", "Research Directorate, Rwanda Military Teaching Hospital, Kigali, Rwanda", "Biomedical Services, National Reference Laboratory, Rwanda Biomedical Center, Kigali, Rwanda", "Exact Sciences Corp., Madison, Wisconsin, United States of America", "Labcorp (formerly Invitae Corp.), San Francisco, California, United States of America", "Division of Cancer Genetics and Prevention, Dana-Farber Cancer Institute, Boston, United States of America", "Division of Medical Oncology, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America", "Harvard Medical School, Boston, Massachusetts, United States of America", "Division of Population Science, Dana Farber Cancer Institute, Boston, Massachusetts, United States of America", "Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, Massachusetts, United States of America" ], "article_type": "Research Article", "arxiv": null, "author_total": 16, "authors": [ { "affs": [ 0 ], "name": "Achille V. C. Manirakiza" }, { "affs": [ 1 ], "name": "Shakuntala Baichoo" }, { "affs": [ 2 ], "name": "Annette Uwineza" }, { "affs": [ 3 ], "name": "Damas Dukundane" }, { "affs": [ 4 ], "name": "Eulade Rugengamanzi" }, { "affs": [ 5 ], "name": "Janviere Mutamuliza" }, { "affs": [ 6 ], "name": "Allison M. O. Niragira" }, { "affs": [ 7 ], "name": "Raissa Muvunyi" }, { "affs": [ 8 ], "name": "Jeffrey Besada" }, { "affs": [ 9 ], "name": "Sarah M. Nielsen" }, { "affs": [ 10 ], "name": "Brianna Bucknor" }, { "affs": [ 11 ], "name": "Diane R. Koeller" }, { "affs": [ 12 ], "name": "Caroline Andrews" }, { "affs": [ 13 ], "name": "Leon Mutesa" }, { "affs": [ 14 ], "name": "Temidayo Fadelu" }, { "affs": [ 15 ], "name": "Timothy R. Rebbeck" } ], "bibtex": "https://research.draconitic.com/paper/3v2ws8fnegdx9.bib", "cited_by": 0, "doi": "10.1371/journal.pgen.1012180", "fulltext_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012180", "id": "3v2ws8fnegdx9", "issns": [ "1553-7404" ], "landing_url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012180", "language": null, "licence": "CC-BY-4.0", "licence_label": "CC BY 4.0", "licence_source": "journal", "licence_url": "https://creativecommons.org/licenses/by/4.0/", "metadata_licence": null, "native_subjects": [ [ "openalex", "1311|BRCA gene mutations in cancer" ], [ "plos", "/Biology and life sciences/Genetics/Genetic loci/Alleles" ], [ "plos", "/Biology and life sciences/Genetics/Heredity" ], [ "plos", "/Biology and life sciences/Genetics/Heredity/Genetic mapping/Haplotypes" ], [ "plos", "/Medicine and health sciences/Diagnostic medicine/Cancer detection and diagnosis" ], [ "plos", "/Medicine and health sciences/Epidemiology/Medical risk factors/Cancer risk factors/Genetic causes of cancer" ], [ "plos", "/Medicine and health sciences/Oncology/Cancer detection and diagnosis" ], [ "plos", "/Medicine and health sciences/Oncology/Cancer risk factors/Genetic causes of cancer" ], [ "plos", "/Medicine and health sciences/Oncology/Cancers and neoplasms/Breast tumors/Breast cancer" ], [ "plos", "/People and places/Geographical locations/Africa/Rwanda" ], [ "plos", "/People and places/Geographical locations/Europe" ] ], "openalex": "W7162766171", "pdf_url": "https://journals.plos.org/plosgenetics/article/file?id=10.1371/journal.pgen.1012180&type=printable", "pmcid": null, "pmid": null, "published": "2026-11-02", "publisher": "Public Library of Science", "ris": "https://research.draconitic.com/paper/3v2ws8fnegdx9.ris", "sources": [ { "first_seen": "2026-11-03T12:20:16Z", "native_id": "10.1371/journal.pgen.1012180", "source": "plos", "url": "https://journals.plos.org/plosgenetics/article?id=10.1371/journal.pgen.1012180" } ], "subjects": [ { "field": "biology", "origin": "plos:genetics", "subfield": "genetics-genomics" }, { "field": "medicine", "origin": "plos:oncology", "subfield": "oncology" } ], "title": "A common pathogenic founder variant in Rwandan breast cancer cases", "title_text": "A common pathogenic founder variant in Rwandan breast cancer cases", "type": "peer-reviewed", "updated_at": "2026-11-04T12:20:44Z", "url": "https://research.draconitic.com/paper/3v2ws8fnegdx9", "venue": "PLOS Genetics", "versions": [] }