Background/Objectives: Compared to single gene testing (SGT), multigene panel testing (MGPT) improves pathogenic variants (PVs) detection. However, MGPT yields complex results, including secondary findings, heterozygous PVs in recessive genes, low-penetrance PVs, and variants of uncertain significance. We reported our mono-institutional experience of germline testing in breast cancer (BC), comparing SGT and MGPT. Methods: We retrospectively analyzed clinical and molecular data from 1084 BC patients: 308 underwent SGT (BRCA1/BRCA2) and 776 MGPT (for 28 cancer-related genes). We compared these approaches regarding the genetic classification of the findings (positive, uncertain, uninformative) and their impact on clinical management (primary findings (PFs); complex and inconclusive results). Additionally, we described clinical features supporting one approach over the other and focused on copy number variation (CNV) frequency in non-BRCAgenes. Results: We found ≥1 PV in 165 patients (165/1084 = 15.2%), including 91 inBRCA1/BRCA2(91/1084 = 8.4%), with 42 identified by SGT (42/308 = 13.6%) and 49 by MGPT (49/776 = 6.3%). MGPT detected PVs in non-BRCAgenes in 74 patients (74/776 = 9.5%), including 40 PFs. Overall, MGPT identified 89 PFs (89/776 = 11.5%). We observed complex results in 21 patients (21/308 = 6.8%) with SGT and in 300 (300/776 = 38.7%) with MGPT. Compared to MGPT, SGT detected a similar percentage of PFs (13.6% vs. 11.5%) but a significantly reduced percentage of complex results (6.8% vs. 38.7%) (p< 0.001). Triple-negative BCs prevailed inBRCA1carriers, while ER-positive BCs were more prevalent inATM/CHEK2carriers. Concerning non-BRCAgenes, MGPT detected CNVs inPALB2, representing 20% of PVs in this gene. Conclusions: Although MGPT increases hereditary BC detection, its complexity requires clear guidelines for optimal clinical management and strategies for merging the benefits of SGT and MGPT.
背景/目的：与单基因检测相比，多基因组合检测提高了致病性变异检出率。然而，多基因组合检测会产生复杂结果，包括次要发现、隐性基因杂合致病性变异、低外显率致病性变异以及意义未明变异。本研究报道了我们在乳腺癌种系检测方面的单中心经验，比较了单基因检测与多基因组合检测的差异。方法：我们回顾性分析了1084例乳腺癌患者的临床和分子数据：其中308例接受单基因检测（BRCA1/BRCA2），776例接受多基因组合检测（涵盖28个癌症相关基因）。我们比较了这两种方法在遗传学结果分类（阳性、不确定、无信息）及其对临床管理的影响（主要发现；复杂和不确定结果）方面的差异。此外，我们描述了支持选择某种检测方法的临床特征，并重点关注了非BRCA基因的拷贝数变异频率。结果：在165例患者中检出≥1个致病性变异（165/1084 = 15.2%），其中91例位于BRCA1/BRCA2基因（91/1084 = 8.4%），包括单基因检测发现的42例（42/308 = 13.6%）和多基因组合检测发现的49例（49/776 = 6.3%）。多基因组合检测在74例患者中检出非BRCA基因致病性变异（74/776 = 9.5%），其中40例为主要发现。总体而言，多基因组合检测共发现89例主要发现（89/776 = 11.5%）。我们观察到单基因检测产生复杂结果21例（21/308 = 6.8%），多基因组合检测产生300例（300/776 = 38.7%）。与多基因组合检测相比，单基因检测的主要发现检出率相近（13.6% vs. 11.5%），但复杂结果比例显著降低（6.8% vs. 38.7%）（p<0.001）。三阴性乳腺癌在BRCA1携带者中占主导，而ER阳性乳腺癌在ATM/CHEK2携带者中更为普遍。在非BRCA基因方面，多基因组合检测在PALB2基因中检出拷贝数变异，占该基因致病性变异的20%。结论：尽管多基因组合检测提高了遗传性乳腺癌检出率，但其复杂性需要制定明确的临床管理指南，并制定整合单基因检测与多基因组合检测优势的策略。
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