Submissions for variant NM_000546.6(TP53):c.536A>T (p.His179Leu)

dbSNP: rs1057519991

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000705316	SCV000834307	uncertain significance	Li-Fraumeni syndrome	2024-06-10	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 179 of the TP53 protein (p.His179Leu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376608). Advanced modeling performed at Invitae incorporating data from internal and/or published 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: 9049183, 12826609, 16861262, 22114072, 23713777). 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.
Ambry Genetics	RCV002348143	SCV002647130	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-06-13	criteria provided, single submitter	clinical testing	The p.H179L variant (also known as c.536A>T), located in coding exon 4 of the TP53 gene, results from an A to T substitution at nucleotide position 536. The histidine at codon 179 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly conserved in available vertebrate species. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially 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 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). Cells carrying this variant were shown to induce tumor formation when transplanted into mice (Cardinali M et al. Mol Carcinog, 1997 Feb;18:78-88). Two other alterations at the same codon, p.H179Q and p.H179R have been described in individuals with TP53-related disease (Petitjean A et al. IARC TP53 database [version R19, August 2018]. Hum Mutat. 2007 Jun;28(6):622-9;Gonzalez KD et al. J. Med. Genet. 2009 Oct; 46(10):689-93). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Baylor Genetics	RCV003476009	SCV004204285	likely pathogenic	Adrenocortical carcinoma, hereditary	2022-02-07	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004022217	SCV004933946	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 9049183, 9049184, 23713777]. This variant is expected to disrupt protein structure [Myriad internal data].
GeneDx	RCV004721352	SCV005327534	likely pathogenic	not provided	2024-01-04	criteria provided, single submitter	clinical testing	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 15510160, 30224644, 16861262, 30661751, 9546439, 12124823, 11590071, 22114072, 29979965, 9049183, 12826609, 23713777, 16633321, 18511570, 19556618, 25433984)