The association between age at breast cancer diagnosis and prevalence of pathogenic variants

PURPOSE: 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. METHODS: 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. RESULTS: 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). CONCLUSIONS: Young age at BC diagnosis is not a strong risk factor for carrying PVs in BC-associated genes ATM, CHEK2, or PALB2. SUPPLEMENTARY INFORMATION: The online version contains supplementary material available at 10.1007/s10549-023-06946-8.