Abstract PS3-03-28: Recurrent, Cryptic BRCA1 Complex Rearrangement by Whole-genome Sequencing in Patients with Breast Cancer

Abstract Introduction: Detecting pathogenic germline variants in BRCA1/2 is crucial for hereditary cancer risk assessment and guiding targeted therapies. While targeted NGS panels are effective for SNVs and indels, they often miss large structural variations (SVs), leading to false negatives. Whole-genome sequencing (WGS) offers a comprehensive solution by providing uniform, genome-wide coverage for robust SV detection. This report presents two clinical cases where WGS identified an identical, complex pathogenic BRCA1 SV missed by conventional panel testing. Methods: DNA was extracted from fresh-frozen tumor tissue and matched normal blood samples from two patients: a 40-year-old premenopausal female with breast and ovarian double primary cancers and a female in her 60s with metastatic pancreatic cancer (history of breast cancer). WGS analysis was performed using the CancerVision™ system. Results: Both patients initially had non-decisive hereditary cancer panel results. WGS revealed an identical, complex pathogenic germline BRCA1 variant in both: a large deletion of exons 12-14 coupled with an adjacent inversion. This BRCA1 deletion was successfully orthogonally confirmed by MLPA. The first patient's breast tumor showed BRCA1 loss of heterozygosity (LOH), a high HRD score (0.93), 40.0% of base substitutions attributed to SBS3 (indicating flawed homologous recombination-based DNA repair), and a high prevalence of SV duplications (45.8%), suggesting a complete BRCA1 defect. The second patient's tumor also showed BRCA1 LOH, 33.7% of base substitutions attributed to SBS3, and high SV duplications (33.7%), collectively suggesting impaired BRCA1 function. This patient achieved and maintained a complete response to platinum-based chemotherapy. Discussion: This study demonstrates WGS's transformative power in resolving clinically important cases missed by conventional genomic approaches. The key finding is the identification of an identical, complex recurrent BRCA1 SV in two unrelated patients, providing definitive molecular diagnoses that significantly impacted clinical management. This recurrence suggests a potential underdiagnosed founder mutation. WGS's unparalleled advantage lies in its uniform, genome-wide coverage, enabling simultaneous detection of diverse genomic variations, including complex SVs, ensuring a comprehensive and unbiased genetic landscape elucidation. WGS provides precise genomic breakpoint locations, allowing unequivocal determination of variant identity across patients and facilitating tracking of origins and population-specific prevalence. These cases underscore WGS's critical role in identifying pathogenic SVs undetectable by standard methods, advocating for its integration into clinical diagnostics for high-risk patients to enhance accuracy and support personalized treatment strategies. Citation Format: B. Oh, S. Choi, S. Seo, H. Park, E. Connolly-Strong, T. Kim, Y. Ju, J. Hwang, Y. Park.. Recurrent, Cryptic BRCA1 Complex Rearrangement by Whole-genome Sequencing in Patients with Breast Cancer [abstract]. In: Proceedings of the San Antonio Breast Cancer Symposium 2025; 2025 Dec 9-12; San Antonio, TX. Philadelphia (PA): AACR; Clin Cancer Res 2026;32(4 Suppl):Abstract nr PS3-03-28.