The American College of Medical Genetics currently recognizes a wide range of germline variants in the gene TP53 as pathogenic or likely pathogenic and causing the inherited disorder, Li-Fraumeni Syndrome.1 Cancers strongly associated with Li-Fraumeni syndrome include common and rare malignancies such as breast cancer, adrenocortical carcinoma, and osteosarcoma, and are normally diagnosed in patients at much younger ages than the average age of diagnosis for the general population.

In July 2020, a team of multidisciplinary researchers led by clinician-scientists at the Abramson Cancer Center at Penn Medicine, Philadelphia, added to the understanding of pathogenic TP53 variants with the publication of study in which they identified a rare, novel variant implicated in the development of Li-Fraumeni syndrome predominantly in families of Ashkenazi Jewish descent.2

Nonpathogenic p53 protein is composed of 4 major protein domains: transactivation, proline-rich, DNA-binding, and tetramerization, and is a transcription factor that activates transcription of genes encoding DNA repair machinery in healthy cells.1 Because p53 functions as a transcriptional regulator, pathogenic mutations in TP53 are most commonly observed in sequences encoding the DNA binding domain, causing the mutant p53 protein to lose its normal capacity to bind to target promoter sequences for transcriptional activation.1 Unlike more common pathogenic mutations in the DNA binding domain, the novel variant, c, 1000G>C;p. G334R, is a pathogenic missense mutation in the tetramerization domain of p53, resulting in disruption of the normal tetramerization of p53 polypeptides required to assume its native structure in wild-type carriers.2

A well-documented example of a pathogenic germline mutation in the tetramerization domain of p53 occurs in 0.3% of the general population in Southern Brazil, where a spectrum of early onset cancers was also observed in the population and confirmed as Li-Fraumeni Syndrome.3


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Discovery of the novel pathogenic variant began with a research sequencing study at Abramson’s Cancer Center aimed at identifying breast cancer susceptibility genes in patients with early-onset disease who were negative for germline pathogenic BRCA1/2 variants.4 Additional families with the TP53 c. 1000G>C; G334R variant were then identified from national databases and testing sites such as the National Society of Genetic Counselors ListServ and commercial genetic testing lab cases such as Ambry Genetics.

The researchers’ case-ascertainment database analyses resulted in a final total of 21 cases of early-onset cancer carrying the novel pathogenic TP53 variant.2 To further validate the pathogenicity of the novel variant, a team of multidisciplinary researchers utilized criteria in the 2015 ACMG/AMP Variant interpretation guidelines to evaluate predictive computational modeling of the mutant protein and in-vitro functional data of the mutant p53 in cells line.1,2