Response to: Concern regarding classification of germlineTP53 variants as likely pathogenic.

Abstract

We appreciate the Letter to the Editor by Evans, Turnbull, and Woodward (2019) on our manuscript “Variable population prevalence estimates of germline TP53 variants: A gnomAD-based analysis” (de Andrade et al., 2019) and would like to take this opportunity to address key aspects of the letter. We agree with the statement by Evans et al. (2019) that clinical considerations related to germline TP53 variant classification are of critical importance. Our article (de Andrade et al., 2019) aimed to conduct a population-level approach to estimate the prevalence of germline TP53 variants in a publicly available database of presumed non-cancer individuals, with its inherent biases and challenges. In our manuscript, nonclinical classification criteria were established for research-purposes to allow for the discovery of potentially deleterious variants. These criteria were not intended for application in the clinical setting of germline TP53 variant curation, nor were they intended to estimate the prevalence of Li-Fraumeni syndrome. We acknowledged this in the Methods section, as follows: “Importantly, these nonclinical classification criteria are independent of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology (ACMG-AMP) guidelines for variant classification (Richards et al., 2015). Therefore, these criteria are not necessarily representative of the more stringent methods utilized when determining the pathogenicity of a variant for clinical use.” (de Andrade et al., 2019). Variant classification is a dynamic process that is dependent on the emergence of novel functional data, bioinformatic prediction tool advancements, and clinical data sharing. This evolving process may ultimately reclassify certain variants, leading to potential changes in the estimated population prevalence of pathogenic/likely pathogenic germline TP53 variants. Robust variant classification combined with clinical criteria is required for a proper diagnosis of Li-Fraumeni syndrome. We would like to highlight that the prevalence of Li-Fraumeni syndrome cannot be determined by the population frequency of pathogenic germline TP53 variants alone. Li-Fraumeni syndrome is a clinical diagnosis on the basis of personal and family history of cancer. As discussed in our manuscript and reinforced herein, germline TP53 variant curation in relation to Li-Fraumeni syndrome should be comprehensively evaluated on the basis of family history, clinical standards, and established clinical variant classification guidelines (Amendola et al., 2016; Richards et al., 2015). Clinical genetic testing, cancer surveillance, and management recommendations for Li-Fraumeni syndrome-associated TP53 variants must be made by specialists after thorough consideration of the individual cancer risk. The authors declare that there are no conflict of interests.