Li-Fraumeni syndrome (LFS) represents an inherited tumor syndrome that is typically caused by germline mutations of the tumor suppressor gene TP53. TP53 dysfunction secondarily disturbs the genetic integrity of the cell. Here, we report a family with LFS harboring a germline TP53 mutation (R248W) located in the functional domain of the protein that binds to the minor groove of the DNA. In this family, tumors of the central nervous system were diagnosed as primary malignancies in all carriers of the mutation. The index patient developed an anaplastic medulloblastoma with unusual genomic profile exhibiting six distinct high-level genomic amplifications, two of them targeting the MYCN and GLI2 genes, respectively. In an extrarenal rhabdoid tumor from the same patient, we found a novel high-level amplification of the MYC oncogene. The father of this patient was diagnosed with myxopapillary ependymoma (WHO degrees I), whereas a brother died from an early relapse of a choroid plexus carcinoma. The analysis of this LFS familiy thus revealed novel oncogene amplifications as different second hits that are likely to also play a role in the pathogenesis of their sporadic counterparts.