Purpose: Lobular breast cancer (LBC) accounts for ~ 15% of breast cancer. Here, we studied the frequency of pathogenic germline variants (PGVs) in an extended panel of genes in women affected with LBC. Methods: 302 women with LBC and 1567 without breast cancer were tested for BRCA1/2 PGVs. A subset of 134 LBC affected women who tested negative for BRCA1/2 PGVs underwent extended screening, including: ATM, CDH1, CHEK2, NBN, PALB2, PTEN, RAD50, RAD51D, and TP53. Results: 35 PGVs were identified in the group with LBC, of which 22 were in BRCA1/2. Ten actionable PGVs were identified in additional genes (ATM(4), CDH1(1), CHEK2(1), PALB2(2) and TP53(2)). Overall, PGVs in three genes conferred a significant increased risk for LBC. Odds ratios (ORs) were: BRCA1: OR = 13.17 (95%CI 2.83–66.38; P = 0.0017), BRCA2: OR = 10.33 (95%CI 4.58–23.95; P < 0.0001); and ATM: OR = 8.01 (95%CI 2.52–29.92; P = 0.0053). We did not detect an increased risk of LBC for PALB2, CDH1 or CHEK2. Conclusion: The overall PGV detection rate was 11.59%, with similar rates of BRCA1/2 (7.28%) PGVs as for other actionable PGVs (7.46%), indicating a benefit for extended panel genetic testing in LBC. We also report a previously unrecognised association of pathogenic variants in ATM with LBC.

目的：小叶乳腺癌（LBC）约占乳腺癌的 15%。在这里，我们研究了受 LBC 影响的女性的一组扩展基因中致病性种系变异 (PGV) 的频率。方法：对 302 名 LBC 女性和 1567 名无乳腺癌女性进行了BRCA1/2 PGV 检测。对BRCA1/2 PGV检测呈阴性的 134 名 LBC 受影响女性进行了扩展筛查，包括：ATM、CDH1、CHEK2、NBN、PALB2、PTEN、RAD50、RAD51D和TP53。 结果：LBC组共鉴定出35个PGV，其中22个在BRCA1/2。在其他基因（ATM (4)、CDH1(1)、CHEK2 (1)、PALB2 (2) 和TP53 (2))。总体而言，三个基因中的 PGV 显着增加了 LBC 的风险。优势比 (OR) 为：BRCA1：OR = 13.17 (95%CI 2.83–66.38；P = 0.0017)，BRCA2：OR = 10.33 (95%CI 4.58–23.95；P < 0.0001)；和ATM： OR = 8.01（95%CI 2.52–29.92；P = 0.0053）。我们没有发现PALB2、CDH1或CHEK2的 LBC 风险增加。结论：总体PGV检出率为11.59%，BRCA1/2检出率相近(7.28%) PGV 与其他可操作的 PGV (7.46%) 一样，表明 LBC 中扩展面板基因检测的益处。我们还报告了以前未被识别的ATM致病变异与 LBC 的关联。