Germline loss-of-function variants in TP53 cause Li-Fraumeni syndrome (LFS) characterized by an early onset of various cancer types including sarcomas, adrenocortical carcinoma, and breast cancer. The most common are mutations in the DNA binding domain of p53, but alterations in the oligomerization domain also cause LFS with variable level of penetrance. Here we report identification of a novel germline in-frame deletion TP53 variant c.1015_1023del p.(E339_F341del) in a family with early-onset breast cancer and other malignancies. Using functional testing, we found that a short deletion in the oligomerization domain in the p.E339_F341del variant severely impaired transcriptional activity of p53 in human cells and in a yeast model. The loss of the transactivation activity was consistent with an observed defect in formation of p53 tetramers. Finally, we found that cells expressing the p.E339_F341del variant were insensitive to inhibition of MDM2 by nutlin-3 confirming the functional defect. We conclude that the in-frame germline c.1015_1023del TP53 variant encodes a transcriptionally inactive protein and promotes LFS with a high penetrant cancer phenotype.

• Keywords
• Cancer, Li Fraumeni syndrome, TP53, p53,
• MeSH
• Adult MeSH
• Genetic Predisposition to Disease * MeSH
• Imidazoles pharmacology   MeSH
• Middle Aged MeSH
• Humans MeSH
• Li-Fraumeni Syndrome * genetics   pathology   MeSH
• Protein Multimerization MeSH
• Tumor Suppressor Protein p53 * genetics   metabolism   chemistry   MeSH
• Breast Neoplasms * genetics   MeSH
• Proto-Oncogene Proteins c-mdm2 metabolism   MeSH
• Pedigree MeSH
• Germ-Line Mutation * MeSH
• Check Tag
• Adult MeSH
• Middle Aged MeSH
• Humans MeSH
• Male MeSH
• Female MeSH
• Publication type
• Journal Article MeSH
• Names of Substances
• Imidazoles MeSH
• Tumor Suppressor Protein p53 * MeSH
• Proto-Oncogene Proteins c-mdm2 MeSH
• TP53 protein, human MeSH Browser