乳腺癌（BC）诊断的年轻年龄和家族历史与BRCA1和BRCA2基因中有致病变异（PVs）的高流行率密切相关。对于ATM、CHEK2和PALB2等中度/高渗透度BC风险基因的这种关联证据有限。我们分析了多基因面板测试结果（09/2013-12/2019）对未受任何癌症影响的女性（N = 371,594）和那些因疑似遗传性乳腺和/或卵巢癌而受影响的BC患者（N = 130,151）。在控制个人/家族非BC历史和自报祖先的情况下，使用多变量逻辑回归检验PV状态与年龄（≤ 45 vs.> 45岁）或乳腺癌家族史的关联。诊断年龄较小（≤ 45岁）和PV存在之间的关联对BRCA1（OR 3.95，95％CI 3.64-4.29）非常强，对BRCA2（OR 1.98，95％CI 1.84-2.14）适中。对于ATM（OR 1.22，95％CI 1.08-1.37）和CHEK2（OR 1.34，95％CI 1.21-1.47）基因，观察到PV和诊断年龄较小之间的适度关联，但对于PALB2（OR 1.12，95％CI 0.98-1.27）不存在。对于BC患者，家族BC诊断年龄最小值遵循类似的模式。对于未受影响的女性，只有BRCA1（OR 2.34，95％CI 2.13-2.56）和BRCA2（OR 1.25，95％CI 1.16-1.35）的家族癌症诊断最小年龄与PV状态显著相关。诊断乳腺癌的年龄较小不是携带ATM、CHEK2或PALB2中BC相关基因中PV的强风险因素。©2023.作者（们）。

Young age at breast cancer (BC) diagnosis and family history of BC are strongly associated with high prevalence of pathogenic variants (PVs) in BRCA1 and BRCA2 genes. There is limited evidence for such associations with moderate/high penetrance BC-risk genes such as ATM, CHEK2, and PALB2.We analyzed multi-gene panel testing results (09/2013-12/2019) for women unaffected by any cancer (N = 371,594) and those affected with BC (N = 130,151) ascertained for suspicion of hereditary breast and/or ovarian cancer. Multivariable logistic regression was used to test association between PV status and age at BC diagnosis (≤ 45 vs. > 45 years) or family history of BC after controlling for personal/family non-BC histories and self-reported ancestry.An association between young age (≤ 45 years) at diagnosis and presence of PVs was strong for BRCA1 (OR 3.95, 95% CI 3.64-4.29) and moderate for BRCA2 (OR 1.98, 95% CI 1.84-2.14). Modest associations were observed between PVs and young age at diagnosis for ATM (OR 1.22, 95% CI 1.08-1.37) and CHEK2 (OR 1.34, 95% CI 1.21-1.47) genes, but not for PALB2 (OR 1.12, 95% CI 0.98-1.27). For women with BC, earliest age of familial BC diagnosis followed a similar pattern. For unaffected women, earliest age of family cancer diagnosis was significantly associated with PV status only for BRCA1 (OR 2.34, 95% CI 2.13-2.56) and BRCA2 (OR 1.25, 95% CI 1.16-1.35).Young age at BC diagnosis is not a strong risk factor for carrying PVs in BC-associated genes ATM, CHEK2, or PALB2.© 2023. The Author(s).