BACKGROUND Approximately 5-10% of breast carcinomas have been related to hereditary conditions and are attributable to pathogenic variants in the BRCA1 and BRCA2 genes, which is referred to as hereditary breast and ovarian cancer (HBOC) syndrome. The inclusion of additional genes that can be related to HBOC syndrome is under intense evaluation due to the high proportion of patients with HBOC criteria who do not present pathogenic mutations in BRCA genes, named BRCAX, despite having high clinical suspicion of hereditary cancer. The main aim is to identify new potentially pathogenic gene variants that may contribute to HBOC to improve the efficiency of routine diagnostic tests in this hereditary condition. METHODS A retrospective cohort of 77 HBOC BRCAX patients was analyzed by next-generation sequencing using a targeted multigene panel composed of 25 genes related to hereditary cancer and deficiencies in DNA repair pathways. RESULTS We found 9 variants in 7 different genes, which were confirmed by automated sequencing. Six variants were classified as pathogenic or likely pathogenic. Three of them were located in the PALB2 gene, one in the BRIP1 gene, one in the BARD1 gene and 1 in the RAD50 gene. In addition, three variants of uncertain significance (VUS) were detected in the TP53, CHEK2, and CDH1 genes. CONCLUSIONS We identified that 8% of BRCAX patients were carriers of pathogenic variants in genes other than BRCA1 and BRCA2. Therefore, wide gene panels, including clinically actionable genes, should be routinely used in the screening of HBOC in our population. We observed differences from other studies in the prevalence of mutated genes, most likely due to differences in the selection criteria of the probands and in the population analyzed. The high incidence of deleterious variant detection in PALB2 supports its significant role in breast cancer susceptibility and reinforces its inclusion in the HBOC genetic diagnostic process.

中文翻译：

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通过下一代测序多基因专家组在BRCAX患者中鉴定DNA损伤修复基因中的种系致病变异。

背景技术大约5-10％的乳腺癌与遗传性疾病有关，并归因于BRCA1和BRCA2基因的致病变异，这被称为遗传性乳腺癌和卵巢癌（HBOC）综合征。由于有很高的遗传性临床怀疑，尽管有HBOC标准的患者中没有出现BRCA基因致病性突变的高比例患者（称为BRCAX），但仍在大量评估中可能包含与HBOC综合征相关的其他基因。主要目的是确定可能导致HBOC的新的潜在致病基因变异，以提高这种遗传状况下常规诊断测试的效率。方法采用靶向多基因组，由25个与遗传性癌症和DNA修复途径相关的基因组成的靶向多基因组，通过下一代测序分析了77例HBOC BRCAX患者的回顾性队列。结果我们在7个不同的基因中发现了9个变异体，这些变异已通过自动测序得以证实。六个变体被分类为致病性或可能致病性。其中三个位于PALB2基因中，一个位于BRIP1基因中，一个位于BARD1基因中，一个位于RAD50基因中。此外，在TP53，CHEK2和CDH1基因中检测到三个不确定性显着性（VUS）变体。结论我们确定了8％的BRCAX患者是BRCA1和BRCA2以外基因的致病变异体的携带者。因此，广泛的基因组，包括临床上可操作的基因，应常规用于筛查我们人群中的HBOC。我们观察到了其他基因突变基因发生率的差异，这很可能是由于先证者的选择标准和所分析人群的差异所致。PALB2中有害变异检测的高发生率支持了其在乳腺癌易感性中的重要作用，并加强了其在HBOC基因诊断过程中的作用。