Submissions for variant NM_000546.6(TP53):c.473G>T (p.Arg158Leu)

dbSNP: rs587782144

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633348	SCV000754570	pathogenic	Li-Fraumeni syndrome	2022-09-15	criteria provided, single submitter	clinical testing	For these reasons, this variant has been classified as Pathogenic. This sequence change replaces arginine, which is basic and polar, with leucine, which is neutral and non-polar, at codon 158 of the TP53 protein (p.Arg158Leu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 25584008; Invitae). ClinVar contains an entry for this variant (Variation ID: 528248). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 25584008, 29979965, 30224644). This variant disrupts the p.Arg158 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 10486318, 17606709, 20455025, 20522432, 23894400, 25584008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
CeGaT Center for Human Genetics Tuebingen	RCV001091169	SCV001247049	pathogenic	not provided	2021-02-01	criteria provided, single submitter	clinical testing
GeneDx	RCV001091169	SCV001823101	pathogenic	not provided	2020-06-12	criteria provided, single submitter	clinical testing	Observed in individuals with a personal or family history consistent with pathogenic variants in this gene (Wasserman 2015, Huang 2018); Published functional studies demonstrate a damaging effect: loss of transcriptional activation, growth suppression, and apoptotic activities; non-functional per IARC database (Kato 2003, Baroni 2004, Dearth 2007, Wasserman 2015, Kotler 2018, IARC); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; Not observed at a significant frequency in large population cohorts (Lek 2016); This variant is associated with the following publications: (PMID: 30840781, 30720243, 29625052, 19756158, 17646286, 20581117, 23117049, 22768918, 15805253, 10753186, 15161705, 15037740, 25584008, 27813088, 14559903, 28843361, 29979965, 16861262, 26723900, 12124823, 25847421, 17606709, 12725534)
Genome-Nilou Lab	RCV002289923	SCV002582597	pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002289922	SCV002583159	pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV002289923	SCV002639139	pathogenic	Hereditary cancer-predisposing syndrome	2024-09-23	criteria provided, single submitter	clinical testing	The p.R158L pathogenic mutation (also known as c.473G>T), located in coding exon 4 of the TP53 gene, results from a G to T substitution at nucleotide position 473. The arginine at codon 158 is replaced by leucine, an amino acid with dissimilar properties. This alteration was identified in a 5 year old patient with adrenal cortical carcinoma and in individuals with early-onset breast cancer, oligoastrocytoma, leiomyosarcoma and lung cancer diagnoses (Wasserman JD et al. J. Clin. Oncol., 2015 Feb;33:602-9; Wong ESY et al. NPJ Genom Med, 2016 Jan;1:15003; Parry EM et al. J Thorac Oncol, 2017 11;12:1673-1678; Huang KL et al. Cell, 2018 04;173:355-370.e14). This variant is in the DNA binding domain of the TP53 protein and is reported to have 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 has deficient transactivation, a dominant negative effect and is deficient at growth suppression (Wong ESY et al. NPJ Genom Med, 2016 Jan;1:15003; Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Another alteration at the same codon, p.R158H (c.473G>A), has been reported in multiple individuals with clinical histories suspicious for Li-Fraumeni syndrome (Varley JM et al. Am J Hum Genet. 1999; 65:995-1006; Villani A et al. Lancet Oncol. 2011 Jun;12(6):559-67; Mitchell G et al. PLoS One. 2013 Jul 22;8(7):e69026; Ruijs MW et al. J Med Genet. 2010 Jun;47(6):421-8; Bougeard GJ et al. J Med Genet. 2008 Aug;45(8):535-8; Wasserman JD et al. J. Clin. Oncol. 2015 Feb;33:602-9; Zerdoumi Y et al. Hum. Mol. Genet. 2017 Jul;26(14):2812; Stjepanovic N et al. BMC Med Genomics. 2018 Aug;11(1):65). The p.R158L 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 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 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 supporting evidence, this alteration is interpreted as a disease-causing mutation.
Myriad Genetics, Inc.	RCV002289922	SCV004932252	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	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: 15037740, 25584008, 10229196]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 21464421, 17308077].