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Correctly identifying the true driver mutations in a patient’s tumor is a major challenge in precision oncology. Most efforts address frequent mutations, leaving medium- and low-frequency variants mostly unaddressed. For  TP53 , this identification is crucial for both somatic and germline mutations, with the latter associated with the Li-Fraumeni syndrome (LFS), a multiorgan cancer predisposition. We present TP53_PROF (prediction of functionality), a gene specific machine learning model to predict the functional consequences of every possible missense mutation in  TP53 , integrating human cell- and yeast-based functional assays scores along with computational scores. Variants were labeled for the training set using well-defined criteria of prevalence in four cancer genomics databases. The model’s predictions provided accuracy of 96.5%. They were validated experimentally, and were compared to population data, LFS datasets, ClinVar annotations and to TCGA survival data. Very high accuracy was shown through all methods of validation. TP53_PROF allows accurate classification of  TP53  missense mutations applicable for clinical practice. Our gene specific approach integrated machine learning, highly reliable features and biological knowledge, to create an unprecedented, thoroughly validated and clinically oriented classification model. This approach currently addresses  TP53  mutations and will be applied in the future to other important cancer genes.

TP53_PROF: a machine learning model to predict impact of missense mutations in TP53