Background/Objectives: GermlineBRCA1mutations account for ~15–20% of hereditary breast and ovarian cancer (HBOC) cases. While most are small sequence variants, structural rearrangements also contribute significantly to the pathogenic landscape. Conventional diagnostic workflows often miss such events, underscoring the need for comprehensive approaches. Here, we report a previously undescribed pathogenic mechanism—a transposon-mediated processed transcript insertion—expanding the mutational spectrum underlying hereditary breast cancer susceptibility.Methods: The studied case was discovered during our germline genotyping routine: next-generation sequencing followed by library preparation with a custom hereditary cancer panel. The identified variant was validated by orthogonal sequencing and multiplex ligation-dependent probe amplification (MLPA). RNA-level functional assays, including nonsense-mediated decay inhibition, were conducted to assess transcript stability. Constitutional origin was confirmed by analysis of multiple normal tissues, and tumor material was evaluated for loss of heterozygosity (LOH).Results: NGS detected a 700 bp insertion in exon 16 ofBRCA1, corresponding to a complete processed transcript ofRPL18A. The insertion caused a frameshift and premature stop codon, triggering degradation of the aberrant transcript. The variant was present in multiple somatic tissues, and its heritable nature was further confirmed by genotyping a first-degree relative, who was also found to carry the insertion. Tumor DNA analysis revealed strong LOH with retention of the variant allele.Conclusions: This study identifies, for the first time, a heritable processed transcript insertion as a pathogenic event inBRCA1. Such variants are undetectable by conventional diagnostic workflows lacking structural variant analysis, highlighting the importance of comprehensive approaches for accurate diagnosis and genetic counselling in hereditary cancer syndromes.
背景/目的：生殖系BRCA1突变约占遗传性乳腺癌和卵巢癌（HBOC）病例的15–20%。其中大多数为小序列变异，但结构重排也在致病谱中占据重要地位。常规诊断流程常遗漏此类事件，凸显了采用全面检测方法的必要性。本研究报道了一种先前未被描述的致病机制——转座子介导的已加工转录本插入，从而扩展了遗传性乳腺癌易感性的突变谱。 方法：研究病例发现于我们的生殖系基因分型常规流程：采用定制遗传性癌症基因组合进行文库构建，随后进行二代测序。通过正交测序和多重连接依赖性探针扩增（MLPA）对鉴定出的变异进行验证。通过包括无义介导的衰变抑制在内的RNA水平功能实验评估转录本稳定性。通过分析多种正常组织确认其体质性起源，并对肿瘤组织进行杂合性缺失（LOH）评估。 结果：二代测序检测到BRCA1基因第16外显子存在700 bp的插入，该序列对应于RPL18A基因的一个完整的已加工转录本。该插入导致移码和提前终止密码子，引发异常转录本的降解。该变异存在于多个体细胞组织中，通过对一级亲属进行基因分型（发现其同样携带该插入）进一步证实了其可遗传性。肿瘤DNA分析显示存在强烈的杂合性缺失，同时保留了该变异等位基因。 结论：本研究首次鉴定出一种可遗传的已加工转录本插入作为BRCA1的致病事件。此类变异在缺乏结构变异分析的常规诊断流程中无法被检测到，这凸显了在遗传性癌症综合征中采用全面方法进行准确诊断和遗传咨询的重要性。
肿瘤(癌症)患者之家