Targeted sequencing approaches, such as conventional cancer panels, often lack coverage of intronic regions. Consequently, gene-disrupting complex genomic rearrangements (CGRs) may go undetected, leading to false-negative results in hereditary cancer testing and limiting access to targeted therapies. Here we report two unrelated cancer patients carrying a novel germline CGR event truncating BRCA1, identified through whole-genome sequencing (WGS). The CGR designated BRCA1 del(e12-14)-inv, comprising deletion and inversion events, removed BRCA1 exons 12–14. Matched tumor genomes further showed loss-of-heterozygosity (LOH) at the locus and mutational signatures supporting homologous recombination deficiency (HRD), confirming the pathogenicity of the germline variant. Our findings suggest that WGS can identify gene-truncating germline CGRs that remain undetected by conventional target-exon–based testing. Of note, detecting these events would be clinically important because they may identify cancer patients who could benefit from PARP inhibitor therapy and may also inform genetic counselling for familial cancer predisposition. These cases highlight the value of WGS for detecting clinically actionable structural variants and support its integration into diagnostic workflows to enhance the clinical utility of genomic medicine.
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