The architecture of TP53, the most frequently mutated gene in human cancer, is more complex than previously thought. Using TP53 variants as clinical biomarkers to predict response to treatment or patient outcome requires an unequivocal and standardized procedure towards a definitive strategy for the clinical evaluation of variants to provide maximum diagnostic sensitivity and specificity. An intronic promoter and two novel exons have been identified resulting in the expression of multiple transcripts and protein isoforms. These regions are additional targets for mutation events impairing the tumor suppressive activity of TP53. Reassessment of variants located in these regions is needed to refine their prognostic value in many malignancies. We recommend using the stable Locus Reference Genomic (LRG) reference sequence for detailed and unequivocal reports and annotations of germ line and somatic alterations on all TP53 transcripts and protein isoforms according the recommendations of the Human Genome Variation Society. This novel and comprehensive description framework will generate standardized data that are easy to understand, analyze and exchange across various cancer variant databases. Based on statistical analysis of more than 45,000 variants in the latest version of the UMD TP53 database, we also provide a classification of their functional effects (“pathogenicity”).This article is protected by copyright. All rights reserved