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A quantitative model to predict pathogenicity of missense variants in the TP53 gene


Germline pathogenic variants in the TP53 gene cause Li-Fraumeni syndrome, a condition that predisposes individuals to a wide range of cancer types. Identification of individuals carrying a TP53 pathogenic variant is linked to clinical management decisions, such as the avoidance of radiotherapy and use of high-intensity screening programs. The aim of this study was to develop an evidence-based quantitative model that integrates independent in silico data (Align-GVGD and BayesDel) and somatic to germline ratio (SGR), to assign pathogenicity to every possible missense variant in the TP53 gene. To do this, a likelihood ratio for pathogenicity (LR) was derived from each component calibrated using reference sets of assumed pathogenic and benign missense variants. A posterior probability of pathogenicity was generated by combining LRs, and algorithm outputs were validated using different approaches. A total of 730 TP53 missense variants could be assigned to a clinically interpretable class. The outputs of the model correlated well with existing clinical information, functional data, and ClinVar classifications. In conclusion, these quantitative outputs provide the basis for individualized assessment of cancer risk useful for clinical interpretation. In addition, we propose the value of the novel SGR approach for use within the ACMG/AMP guidelines for variant classification.

Type Journal
ISBN 1059-7794
Authors Fortuno, C.; Cipponi, A.; Ballinger, M. L.; Tavtigian, S. V.; Olivier, M.; Ruparel, V.; Haupt, Y.; Haupt, S.; Study, I. S. K.; Tucker, K.; Spurdle, A. B.; Thomas, D. M.; James, P. A.
Responsible Garvan Author Prof David Thomas
Published Date 2019-06-01
Published Volume 40
Published Issue 6
Published Pages 788-800
Status Published in-print
DOI 10.1002/humu.23739
URL link to publisher's version