Samenvatting

The architecture of TP 53 , the most frequently mutated gene in human cancer, is more complex than previously thought. Using TP 53 variants as clinical biomarkers to predict response to treatment or patient outcome requires an unequivocal and standardized procedure toward 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 TP 53 . Reassessment of variants located in these regions is needed to refine their prognostic value in many malignancies. We recommend using the stable L ocus R eference G enomic reference sequence for detailed and unequivocal reports and annotations of germ line and somatic alterations on all TP 53 transcripts and protein isoforms according to the recommendations of the H uman G enome V ariation S ociety. 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 the statistical analysis of more than 45,000 variants in the latest version of the UMD TP 53 database, we also provide a classification of their functional effects (“pathogenicity”).