PURPOSE Gross duplications are ambiguous in terms of clinical interpretation due to the limitations of the detection methods that cannot infer their context, namely, whether they occur in tandem or are duplicated and inserted elsewhere in the genome. We investigated the proportion of gross duplications occurring in tandem in breast cancer predisposition genes with the intent of informing their classifications. METHODS The DNA breakpoint assay (DBA) is a custom, paired-end, next-generation sequencing (NGS) method designed to capture and detect deep-intronic DNA breakpoints in gross duplications in BRCA1, BRCA2, ATM, CDH1, PALB2, and CHEK2. RESULTS DBA allowed us to ascertain breakpoints for 44 unique gross duplications from 147 probands. We determined that the duplications occurred in tandem in 114 (78%) carriers from this cohort, while the remainder have unknown tandem status. Among the tandem gross duplications that were eligible for reclassification, 95% of them were upgraded to pathogenic. CONCLUSION DBA is a novel, high-throughput, NGS-based method that informs the tandem status, and thereby the classification of, gross duplications. This method revealed that most gross duplications in the investigated genes occurred in tandem and resulted in a pathogenic classification, which helps to secure the necessary treatment options for their carriers.

中文翻译：

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DNA 断点分析显示，大多数总重复发生在减少乳腺癌易感基因中的 VUS 分类的同时。

目的 由于无法推断其背景的检测方法的局限性，总重复在临床解释方面是模棱两可的，即它们是串联发生还是被复制并插入基因组的其他地方。我们调查了在乳腺癌易感基因中串联发生的总重复的比例，目的是为它们的分类提供信息。方法 DNA 断点测定 (DBA) 是一种定制的双端测序 (NGS) 方法，旨在捕获和检测 BRCA1、BRCA2、ATM、CDH1、PALB2 和 CHEK2 中的总重复中的深内含子 DNA 断点. 结果 DBA 允许我们确定来自 147 个先证者的 44 个独特的总重复的断点。我们确定重复发生在该队列的 114 名（78%）携带者中，而其余的则具有未知的串联状态。在符合重新分类条件的串联总重复中，其中 95% 被升级为致病性。结论 DBA 是一种新颖的、高通量的、基于 NGS 的方法，它可以告知串联状态，从而对总重复进行分类。这种方法表明，所研究基因中的大多数总重复是串联发生的，并导致了致病性分类，这有助于为其携带者确保必要的治疗选择。