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Journal of Breast Cancer Research

ISSN: 2769-2418

Original Research Open Access
Volume 5 | Issue 1 | DOI: https://doi.org/10.46439/breastcancer.5.032

A rare BRCA1 alternative missense mutation identified in African American women with breast cancer

Desta Beyene1, Luisel J. Ricks-Santi2, Delisha A. Stewart3, Muneer Abbas3, Andrea Hayes-Dixon4, Ahmed Ali5, Olakunle O. Kassim3, Robin Williams5, Steven Nagel5, Babak Shokrani6, Robert L. Copeland1,7, Yasmine M. Kanaan1,3,*
  • 1Howard University Cancer Center, Howard University, Washington DC, U.S.A
  • 2Community Health, Education, and Training, Macon and Joan Brock Virginia Health Sciences Old Dominion University, Norfolk, VA, U.S.A
  • 3Department of Microbiology, Howard University College of Medicine, Howard University, Washington DC, U.S.A
  • 4Howard University College of Medicine, Howard University, Washington DC, U.S.A
  • 5Department of Surgery, Howard University Hospital, Washington DC, U.S.A
  • 6Department of Pathology, Howard University Hospital, Washington DC, U.S.A
  • 7Department of Pharmacology, Howard University College of Medicine, Howard University, Washington DC, U.S.A
+ Affiliations - Affiliations

Corresponding Author

Yasmine M. Kanaan, ymkanaan@howard.edu

Received Date: August 05, 2025

Accepted Date: September 11, 2025

Citation:

Beyene D, Ricks-Santi LJ, Stewart DA, Abbas M, Hayes-Dixon A, Ali A, et al. A rare BRCA1 alternative missense mutation identified in African American women with breast cancer. J Breast Cancer Res. 2025;5(1):54-62.


Copyright: © 2025 Beyene D, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.

Abstract

Introduction: Hereditary breast cancer is most commonly caused by inherited mutations in the BRCA1 or BRCA2 genes, which significantly increase the risk of breast and ovarian cancers.

Methods: Denaturing High-Performance Liquid Chromatography (DHPLC) and DNA sequencing were used to analyze BRCA1 mutations, missense variants, polymorphisms, haplotypes, and large genomic rearrangements in ninety-nine African American (AA) patients from high-risk families. Sorting Intolerant From Tolerant (SIFT) analysis was applied to predict the functional impact of amino acid substitutions. Potential effects on splicing were evaluated by examining disruption of conserved exonic splicing enhancer (ESE) elements or canonical splice site sequences. 

Results: DHPLC and sequencing analysis identified a deleterious protein-truncating BRCA1 mutation, 5296delGAAA, in two unrelated patients diagnosed with bilateral and early-onset breast cancer, both with extensive family histories of breast and ovarian cancers. A second pathogenic variant, IVS16+6T>C, was detected in two additional patients with early-onset or bilateral breast cancer and a strong familial history. Three missense variants (Ile379Met, Glu1210Lys, Glu1794Asp), predicted to be deleterious by SIFT, were identified, including two exon 22 variants (Gln1785His and Glu1794Asp) likely to affect splicing. A rare silent variant, 884G>A (Glu255), located in an alternative exon 11 ESE, was identified in one patient and is predicted to abolish tissue-specific splicing. Multiple coding and non-coding polymorphisms were detected, and haplotype analysis revealed two predominant BRCA1 haplotypes among 64% of AA patients, suggesting population-specific allele distributions. MLPA analysis of 26 patients heterozygous for the BRCA1 exon 11 Pro871Leu polymorphism revealed a novel large deletion encompassing exons 1a, 1b, and 2, extending into the promoter region. This deletion, supported by linkage disequilibrium analysis, represents the first report of such a mutation in an AA family. Preliminary MLPA screening of an additional 40 patients and 2 cancer-free controls identified a potential exon 17 duplication in one case, warranting further investigation.

Conclusion: These findings highlight the complexity and diversity of BRCA1 alterations in AA breast cancer patients and underscore the importance of comprehensive genetic screening in this population to enhance risk assessment and guide clinical management.

Keywords

BRCA1, Breast Cancer, African American, Missense mutation

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