High prevalence of cancer-associated TP53 variants in the gnomAD database: A word of caution concerning the use of variant filtering.

The 1,000 genome project, the Exome Aggregation Consortium (ExAC) or the Genome Aggregation database (gnomAD) datasets, were developed to provide large-scale reference data of genetic variations for various populations to filter out common benign variants and identify rare variants of clinical importance based on their frequency in the human population. Using a TP53 repository of 80,000 cancer variants, as well as TP53 variants from multiple cancer genome projects, we have defined a set of certified oncogenic TP53 variants. This specific set has been independently validated by functional and in silico predictive analysis. Here we show that a significant number of these variants are included in gnomAD and ExAC. Most of them correspond to TP53 hotspot variants occurring as somatic and germline events in human cancer. Similarly, disease-associated variants for five other tumor suppressor genes, including BRCA1, BRCA2, APC, PTEN, and MLH1, have also been identified. This study demonstrates that germline TP53 variants in the human population are more frequent than previously thought. Furthermore, population databases such as gnomAD or ExAC must be used with caution and need to be annotated for the presence of oncogenic variants to improve their clinical utility.