TP53 NM_000546.6:c.535C>T, His179Tyr

This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 16633321]. Functional studies indicate this variant impacts protein function [PMID: 12509279, 17530187]. This variant is expected to disrupt protein structure [Myriad internal data].

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com.

The p.H179Y pathogenic mutation (also known as c.535C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 535. The histidine at codon 179 is replaced by tyrosine, an amino acid with similar properties. This mutation has been reported in the germline of multiple individuals with Li-Fraumeni syndrome (Lefrou L et al. Gastroenterol. Clin. Biol., 2006 Mar;30:484-6; Bougeard G et al. J. Clin. Oncol., 2015 Jul;33:2345-52; Zerdoumi Y et al. Hum. Mol. Genet., 2017 Jul;26:2591-2602). Numerous functional assays conducted in yeast and mammalian cells have shown the p.Y179H variant has decreased transactivation activity compared to wild type, and exerts a dominant negative effect (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9, Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98; Scian MJ et al. Oncogene, 2004 May;23:4430-43). Further functional studies indicate this mutation has oncogenic properties through upregulation of genes involved in cell cycle progression and proliferation (Ko JL et al. DNA Repair Amst; Yang D et al. Mol. Cell. Biochem., 2007 Oct;304:219-26; Scian MJ et al. Oncogene, 2004 May;23:4430-43). 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 alteration is located in the DNA binding domain, and is one of four residues necessary to bind the zinc molecule that stabilizes the beta sheet structure of the p53 protein (Martin AC et al. Hum. Mutat. 2002 Feb; 19(2):149-64). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). In addition, another alteration at this same position, p.H179Q was identified as a de novo mutation in a patient with two Li-Fraumeni core cancers (Gonzalez KD et al. J. Med. Genet. 2009 Oct; 46(10):689-93). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.

This sequence change replaces histidine, which is basic and polar, with tyrosine, which is neutral and polar, at codon 179 of the TP53 protein (p.His179Tyr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with a personal and/or family history of Li-Fraumeni syndrome (PMID: 16633321, 18511570, 25433984). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 127815). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 11896595, 12509279, 12726864, 12826609, 17530187, 26497680). For these reasons, this variant has been classified as Pathogenic.