*Article* **Association between Predicted Effects of** *TP53* **Missense Variants on Protein Conformation and Their Phenotypic Presentation as Li-Fraumeni Syndrome or Hereditary Breast Cancer**

**Yaxuan Liu 1,\* , Olga Axell 1, Tom van Leeuwen <sup>2</sup> , Robert Konrat 3, Pedram Kharaziha 1, Catharina Larsson 1, Anthony P. H. Wright 2,† and Svetlana Bajalica-Lagercrantz 1,†**


**Abstract:** Rare germline pathogenic *TP53* missense variants often predispose to a wide spectrum of tumors characterized by Li-Fraumeni syndrome (LFS) but a subset of variants is also seen in families with exclusively hereditary breast cancer (HBC) outcomes. We have developed a logistic regression model with the aim of predicting LFS and HBC outcomes, based on the predicted effects of individual *TP53* variants on aspects of protein conformation. A total of 48 missense variants either unique for LFS (*n* = 24) or exclusively reported in HBC (*n* = 24) were included. LFS-variants were overrepresented in residues tending to be buried in the core of the tertiary structure of TP53 (*p* = 0.0014). The favored logistic regression model describes disease outcome in terms of explanatory variables related to the surface or buried status of residues as well as their propensity to contribute to protein compactness or protein-protein interactions. Reduced, internally validated models discriminated well between LFS and HBC (C-statistic = 0.78−0.84; equivalent to the area under the ROC (receiver operating characteristic) curve), had a low risk for over-fitting and were well calibrated in relation to the known outcome risk. In conclusion, this study presents a phenotypic prediction model of LFS and HBC risk for germline *TP53* missense variants, in an attempt to provide a complementary tool for future decision making and clinical handling.

**Keywords:** Li-Fraumeni syndrome; hereditary breast cancer; germline *TP53* missense variants; quantitative prediction model; protein conformation
