rs587782144

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_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 variant affecting the same amino acid position, but resulting in a different missense (i.e. R158H) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 6.8e-7 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7

Conservation

PhyloP100: 7.91

Variant links:

Genes affected

TP53 (HGNC:11998): (tumor protein p53) This gene encodes a tumor suppressor protein containing transcriptional activation, DNA binding, and oligomerization domains. The encoded protein responds to diverse cellular stresses to regulate expression of target genes, thereby inducing cell cycle arrest, apoptosis, senescence, DNA repair, or changes in metabolism. Mutations in this gene are associated with a variety of human cancers, including hereditary cancers such as Li-Fraumeni syndrome. Alternative splicing of this gene and the use of alternate promoters result in multiple transcript variants and isoforms. Additional isoforms have also been shown to result from the use of alternate translation initiation codons from identical transcript variants (PMIDs: 12032546, 20937277). [provided by RefSeq, Dec 2016]

TP53 links:

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ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 18 ACMG points.

PM1

In a strand (size 9) in uniprot entity P53_HUMAN there are 5 pathogenic changes around while only 0 benign (100%) in NM_000546.6

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7675139-C-T is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.993

PP5

Variant 17-7675139-C-A is Pathogenic according to our data. Variant chr17-7675139-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 528248.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.473G>T	p.Arg158Leu	missense_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.473G>T	p.Arg158Leu	missense_variant	5/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD3 exomes

AF:

0.00000398

AC:

AN:

251268

Hom.:

AF XY:

0.00000736

AC XY:

AN XY:

135852

show subpopulations

Gnomad AFR exome

AF:

0.0000616

Gnomad AMR exome

AF:

0.00

Gnomad ASJ exome

AF:

0.00

Gnomad EAS exome

AF:

0.00

Gnomad SAS exome

AF:

0.00

Gnomad FIN exome

AF:

0.00

Gnomad NFE exome

AF:

0.00

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461880

Hom.:

Cov.:

AF XY:

0.00000138

AC XY:

AN XY:

727240

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.00

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

8.99e-7

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

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	CeGaT Center for Human Genetics Tuebingen	Feb 01, 2021	- -
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) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
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. -

Li-Fraumeni syndrome

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

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: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.99

BayesDel_addAF

Pathogenic

0.57

BayesDel_noAF

Pathogenic

0.58

CADD

Uncertain

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D

Eigen

Uncertain

0.43

Eigen_PC

Uncertain

0.27

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Pathogenic

0.99

D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D;D;D

M_CAP

Pathogenic

0.79

MetaRNN

Pathogenic

0.99

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D

MetaSVM

Pathogenic

0.94

MutationAssessor

Pathogenic

3.2

.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.55

PROVEAN

Pathogenic

-6.8

D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D

REVEL

Pathogenic

0.89

Sift

Pathogenic

0.0

D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D

Sift4G

Pathogenic

0.0010

D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;.;.

Polyphen

1.0

D;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.;D;.

Vest4

0.95

MutPred

0.93

Loss of methylation at R158 (P = 0.0308);Loss of methylation at R158 (P = 0.0308);.;.;.;.;Loss of methylation at R158 (P = 0.0308);.;Loss of methylation at R158 (P = 0.0308);Loss of methylation at R158 (P = 0.0308);Loss of methylation at R158 (P = 0.0308);.;.;Loss of methylation at R158 (P = 0.0308);.;.;.;.;Loss of methylation at R158 (P = 0.0308);

MVP

1.0

MPC

1.8

ClinPred

1.0

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.87

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.0

Details are displayed if max score is > 0.2

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

Publications

LitVar

Below is the list of publications found by LitVar. It may be empty.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

LitVar

Other links and lift over