Submissions for variant NM_000546.6(TP53):c.535C>G (p.His179Asp)

dbSNP: rs587780070

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV001851020	SCV002230464	pathogenic	Li-Fraumeni syndrome	2023-08-02	criteria provided, single submitter	clinical testing	This variant disrupts the p.His179 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 11896595, 12509279, 12726864, 12826609, 16633321, 17530187, 18511570, 25433984, 26497680). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 376610). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 32658383; Invitae). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces histidine, which is basic and polar, with aspartic acid, which is acidic and polar, at codon 179 of the TP53 protein (p.His179Asp). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV002348144	SCV002645091	likely pathogenic	Hereditary cancer-predisposing syndrome	2023-08-02	criteria provided, single submitter	clinical testing	The p.H179D variant (also known as c.535C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 535. The histidine at codon 179 is replaced by aspartic acid, an amino acid with similar properties. This alteration has been reported as a de novo alteration in a male with no tumor history from a cohort of known TP53 mutation carriers (Renaux-Petel M et al. J. Med. Genet., 2018 03;55:173-180). This alteration has also been reported in a patient with a personal history of rhabdomyosarcoma of embryonal anaplastic subtype diagnosed at age 3 (Pondrom M et al. Pediatr Blood Cancer, 2020 Sep;67:e28486). This variant is in the DNA binding domain of the TP53 protein and is reported to have partial loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Additional 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). In addition, other alterations at this same position, p.H179Q (c.537T>A) and p.H179Q (c.537T>G), have been identified as de novo and/or in patients with features suggestive of Li-Fraumeni or Li-Fraumeni-like syndrome (Bougeard G et al. J Med Genet. 2008 Aug;45(8):535-8; Gonzalez KD et al. J. Med. Genet. 2009 Oct; 46(10):689-93; Sheng S et al. Int. J. Cancer, 2020 01;146:487-495). This amino acid position is highly conserved in available vertebrate species. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465649	SCV002760884	likely pathogenic	not specified	2024-11-01	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV003335320	SCV004045022	pathogenic	Li-Fraumeni syndrome 1	2023-06-13	criteria provided, single submitter	clinical testing	This variant is considered pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21590121, 29070607, 32658383].
Baylor Genetics	RCV003470376	SCV004206262	likely pathogenic	Adrenocortical carcinoma, hereditary	2024-01-23	criteria provided, single submitter	clinical testing