ClinVar

Description

This pathogenic variant is denoted TP53 c.818G>A at the cDNA level and p.Arg273His (R273H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). TP53 Arg273His has been reported in individuals with various types of Li Fraumeni-associated cancers, including adrenocortical carcinoma, choroid plexus carcinoma, sarcomas, gastric carcinoma, breast cancer, uterine serous cancer, and leukemia (Malkin 1992, Bemis 2007, Curry 2011, Masciari 2011, Melhem-Bertrandt 2012, Pennington 2013, Wasserman 2015, Schlegelberger 2015). This variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). Additionally, other in vitro-based functional assays have demonstrated that TP53 Arg273His results in severely deficient transactivation activity and exerts a dominant-negative effect over wild-type p53 (Dong 2007, Malcikova 2010, Monti 2011, Wang 2013, Wasserman 2015). TP53 Arg273His was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In-silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.