TP53 NM_000546.6:c.373A>C, Thr125Pro

This variant is considered likely pathogenic. This variant is expected to disrupt protein structure [Myriad internal data]. Functional studies indicate this variant impacts protein function [PMID: 29979965].

The p.T125P variant (also known as c.373A>C), located in coding exon 3 of the TP53 gene, results from an A to C substitution at nucleotide position 373. The threonine at codon 125 is replaced by proline, an amino acid with highly similar properties. This alteration was identified in an individual diagnosed with osteosarcoma (Mirabello L et al. J Natl Cancer Inst, 2015 Jul;107:). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic.

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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609). This missense change has been observed in individual(s) with medulloblastoma and/or osteosarcoma (PMID: 25896519, 29753700; Invitae). This sequence change replaces threonine, which is neutral and polar, with proline, which is neutral and non-polar, at codon 125 of the TP53 protein (p.Thr125Pro). This variant is not present in population databases (gnomAD no frequency). ClinVar contains an entry for this variant (Variation ID: 376666). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive.