ClinVar Genomic variation as it relates to human health

Published functional studies demonstrate a damaging effect: non-functional transactivation and loss of growth suppression activity (Kato 2003, Kotler 2018) and very weak transactivation in a system in which TP53 activity is increased (Jordan 2010); Observed in individuals with TP53-related cancers referred for genetic testing at GeneDx and in published literature (Melhem-Bertrandt 2012, Churpek 2015, and Mirabello 2015); Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 29979965, 30720243, 20407015, 25896519, 25428789, 21761402, 30840781)

This sequence change replaces proline with alanine at codon 278 of the TP53 protein (p.Pro278Ala). The proline residue is highly conserved and there is a small physicochemical difference between proline and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 21761402, 25428789, 25896519, 27328919; Invitae). ClinVar contains an entry for this variant (Variation ID: 376645). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. Experimental studies have shown that this variant affects TP53 protein function (PMID: 12826609, 20407015, 24076587, 29979965, 30224644). This variant disrupts the p.Pro278 amino acid residue in TP53. Other variant(s) that disrupt this residue have been observed in individuals with TP53-related conditions (PMID: 8688334, 11370630), which suggests that this may be a clinically significant amino acid residue. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

The p.P278A variant (also known as c.832C>G), located in coding exon 7 of the TP53 gene, results from a C to G substitution at nucleotide position 832. The proline at codon 278 is replaced by alanine, an amino acid with highly similar properties. This alteration has been identified in a patient meeting Chompret criteira (personal communication). This alteration has also been reported in a 1 of 109 women diagnosed with breast cancer who underwent genetic testing for suspected germline TP53 mutations (Melhem-Bertrandt A et al. Cancer. 2012 Feb;118:908-13). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in functional studies in yeast and human cell lines (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Jordan JJ et al. Mol. Cancer Res., 2010 May;8:701-16; Wang B et al. Cell Death Differ., 2014 Apr;21:521-32). Additional studies showed this variant to be deficient in DNA binding, apoptosis induction, and growth suppression (Wang B et al. Cell Death Differ. 2014 Apr;21:521-32; Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8). Other alterations at this same amino acid position (p.P278S, p.P278T) have previously been reported in the germline of individuals diagnosed with Li-Fraumeni syndrome (Bougeard G et al. J. Med. Genet. 2001 Apr; 38(4):253-7; Güran S et al. Cancer Genet. Cytogenet. 2005 Jul; 160(2):164-8; Speiser P et al. Br. J. Cancer. 1996 Jul; 74(2):269-73). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in DNA binding (Petty TJ et al. EMBO J. 2011 Jun;30:2167-76; Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.