Abstract Background Li-Fraumeni syndrome (LFS), a hereditary condition attributed to TP53 pathogenic variants,(PV), is associated with high risks for various malignant tumors, including breast cancer. Notably, individuals harboring TP53 PVs are more likely (67–83%) to develop HER2 + breast cancer than noncarriers (16–25%). In this retrospective study, we evaluated the associations between TP53 variants and breast cancer phenotype. Methods We conducted a retrospective review of the medical records of patients with LFS treated at a single institution and reviewed the literature on TP53 functions and the mechanisms underlying HER2 + breast cancer development in LFS. Results We analyzed data for 10 patients with LFS from 8 families. The median age at the onset of the first tumor was 35.5 years. Only case 2 met the classic criteria; this patient harbored a nonsense variant, whereas the other patients carried missense variants. We observed that 9 of 10 patients developed breast cancer. Immunohistochemical analyses revealed that 40% of breast cancers in patients with LFS were HR − /HER2 + . The median age at the onset of breast cancer was slightly younger in HR − /HER2 + tumors than in HR + /HER2 − tumors (31 years and 35.5 years, respectively). Conclusions The occurrence of HER2 + breast cancer subtype was 40% in our LFS case series, which is greater than that in the general population (16–25%). Some TP53 PVs may facilitate HER2-derived oncogenesis in breast cancer. However, further studies with larger sample sizes are warranted to clarify the oncogenic mechanisms underlying each subtype of breast cancer in TP53 PV carriers.