Submissions for variant NM_000546.6(TP53):c.578A>G (p.His193Arg)

dbSNP: rs786201838

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164329	SCV000214960	pathogenic	Hereditary cancer-predisposing syndrome	2024-10-14	criteria provided, single submitter	clinical testing	The p.H193R pathogenic mutation (also known as c.578A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 578. The histidine at codon 193 is replaced by arginine, an amino acid with highly similar properties. This variant has previously been reported in an individual from a family meeting classic Li Fraumeni syndrome criteria, in an individual meeting Chompret criteria, and in several unrelated individuals with early onset Li-Fraumeni spectrum tumors (Frebourg T et al. Am. J. Hum. Genet. 1995 Mar; 56(3):608-15; Nandikolla AG et al. Breast Cancer (Dove Med Press), 2017 Mar;9:207-215; Fortes FP et al. Braz. J. Med. Biol. Res. 2015 Jul;48:610-5; Bouaoun L et al. IARC TP53 database [version R18, April 2016]. Hum. Mutat. 2016 Sep;37:865-76). This alteration has also been reported in multiple breast cancer cohorts (Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Li JY et al. Int J Cancer, 2019 01;144:281-289; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays, a dominant negative effect, and reduced DNA binding activity (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98). 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). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
GeneDx	RCV000255425	SCV000322118	pathogenic	not provided	2023-12-12	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: 17606709, 9627118, 15280671, 7887414, 19367569, 20128691, 21343334, 26425688, 9546439, 16322298, 16861262, 11238194, 21190917, 1458490, 30816478, 25945745, 29752822, 28724667, 30720243, 30840781, 31105275, 32817165, 15161705, 22265402, 30076369, 30224644, 29979965, 15510160, 28356770, 12826609)
Labcorp Genetics (formerly Invitae), Labcorp	RCV000460847	SCV000545345	pathogenic	Li-Fraumeni syndrome	2024-10-02	criteria provided, single submitter	clinical testing	This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 193 of the TP53 protein (p.His193Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome-associated tumors (PMID: 7887414, 22265402, 25945745, 28724667; internal data). ClinVar contains an entry for this variant (Variation ID: 184979). 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: 9627118, 12826609, 16861262, 20128691, 21343334). For these reasons, this variant has been classified as Pathogenic.
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo	RCV000429618	SCV001450485	pathogenic	Squamous cell carcinoma of the head and neck		criteria provided, single submitter	case-control
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255425	SCV001469323	likely pathogenic	not provided	2020-09-01	criteria provided, single submitter	clinical testing	The variant has been reported in individuals with Li-Fraumeni syndrome related cancers in the published literature (PMID: 29752822 (2018), 28724667 (2017), 25945745 (2015), 22265402 (2012), 17606709 (2007), 7887414 (1995)). Functional data indicates that this variant acts in a dominant negative manner and disrupts the transcriptional transactivation and DNA binding activity of the TP53 protein (PMID: 21343334 (2011), 20128691 (2010), 16861262 (2007), 12826609 (2003), 9627118 (1998)). Based on the available information, we predict that the variant is likely pathogenic.
Genome-Nilou Lab	RCV000164329	SCV002582375	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288732	SCV002583036	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003474857	SCV004204277	pathogenic	Adrenocortical carcinoma, hereditary	2022-08-09	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV002288732	SCV004930956	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-15	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15221755, 20128691, 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: 7887414, 28356770].
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785346	SCV000923914	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research