Data from The Biology of Hypomorphic <i>TP53</i> Variants and Implications for Clinical Management

<jats:p>&lt;div&gt;Abstract&lt;p&gt;In individuals with classic Li-Fraumeni syndrome (LFS) due to a loss-of-function pathogenic germline variant in &lt;i&gt;TP53&lt;/i&gt;, loss of p53 tumor suppressive function leads to a high risk of childhood cancers such as sarcomas, adrenal cortical carcinomas, brain tumors, and leukemia. In adults with classic LFS, in addition to the classical malignancies, breast cancers and other cancers develop at earlier ages of onset compared with individuals without LFS. Increased genetic testing is identifying a higher frequency of germline &lt;i&gt;TP53&lt;/i&gt; variants with conflicting interpretations in clinical databases, some of which are likely hypomorphic or of atypical penetrance. Studies of these hypomorphic &lt;i&gt;TP53&lt;/i&gt; variants reveal differential retention or loss of the myriad of p53 tumor-suppressive functions. Many individuals with hypomorphic &lt;i&gt;TP53&lt;/i&gt; variants develop cancer, including both canonical and common types, though at later ages compared with classic LFS. Therefore, further study is needed to understand the most critical tumor suppressive functions of p53, as are data-driven clinical guidelines for the management of cancer risk. Herein, we review models of &lt;i&gt;TP53&lt;/i&gt; variant classification, focusing on strategies to identify hypomorphic &lt;i&gt;TP53&lt;/i&gt; variants. We go on to review the biology and clinical phenotypes of &lt;i&gt;TP53&lt;/i&gt; hypomorphic variants that have detailed reports of their effects on p53 tumor-suppressive functions. Using this framework, we propose possible modifications to the standard LFS screening protocol for individuals with hypomorphic &lt;i&gt;TP53&lt;/i&gt; variants that should be studied in prospective clinical trials.&lt;/p&gt;&lt;/div&gt;</jats:p>