rs587782144
Variant summary
Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_StrongPM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.473G>T(p.Arg158Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,880 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another nucleotide change resulting in same amino acid change has been previously reported as Likely pathogenicin ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R158C) has been classified as Likely pathogenic.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 26 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.473G>T | p.Arg158Leu | missense_variant | 5/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.473G>T | p.Arg158Leu | missense_variant | 5/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251268Hom.: 0 AF XY: 0.00000736 AC XY: 1AN XY: 135852
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461880Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727240
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:2
Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 14, 2024 | 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]. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Jun 12, 2020 | 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) - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Feb 01, 2021 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 19, 2021 | The p.R158L variant (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 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. - |
Pathogenic, criteria provided, single submitter | clinical testing | Genome-Nilou Lab | Jun 18, 2022 | - - |
Li-Fraumeni syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Sep 15, 2022 | For these reasons, this variant has been classified as Pathogenic. 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 25584008, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 528248). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 25584008; Invitae). This variant is not present in population databases (gnomAD no frequency). 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). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at