Germline mutations of p53 tumor gene linked to Li-Fraumeni syndrome (LFS) are associated with an increased risk of cancer

Abstract Choroid plexus carcinomas (CPCs) are rare pediatric tumors often associated with Li-Fraumeni Syndrome (LFS). In LFS, TP53 mutations are involved. A germline mutation in the TP53 gene has been found in about three-quarters of families with Li-Fraumeni syndrome and one-quarter of families with Li-Fraumeni-like syndrome. LFS is a complex predisposition to inherited cancer associated with early cancer in different tissues. BRCA1 and BRCA2 mutations are also more likely to carry TP53 mutations. It has been reported that TP53: 799C>T, p. (Arg267Trp) has been identified as a rare missense mutation in a Saudi family by Musa AlHarbi, 2018. This mutation we further identified to confirm the structural and functional significance. Germline TP53 mutations are identified in 75 % of patients associated with classic LFS. The lifetime likelihood of a TP53 mutation carrier developing cancer approaches 75 % in males and almost 100 % in females. Overall, 75 % of families with classic LFS have significant clinical variants in the tumor suppressor gene TP53 that might disrupt protein function and stability determined by different algorithms. The results of this mutation cytogenetic location on 17p13.1: NM_000546.6 (TP53): c. 799C>T, p. (Arg267Trp) structurally affect H- bond formation. The wild type residue forms a salt bridge with glutamic acid at position 258. The difference in charge will disturb the ionic interaction made by the wild type residue Arg267. This mutation was located within a stretch of residues annotated in UniProt as a unique region interaction with Cell Cycle And Apoptosis Regulator 2 (CCAR2). Also, amino acid properties can disturb this region and function. It might be possible that the mutation disturbs this interaction and thereby affects the regulation of catalytic enzyme activity. Moreover, the results reported herein strengthen the intermolecular interactions in TP53 activity and provide useful information for the design of appropriate of any mutants.