rs587782144

Positions:

• chr17-7675139-C-A
• chr17-7675139-C-G
• chr17-7675139-C-T

Variant summary

Our verdict is Pathogenic. Variant got 26 ACMG points: 26P and 0B. PS1_Very_Strong PM1 PM2 PM5 PP3_Strong PP5_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:
  • Genomes: not found (cov: 33)
  • Exomes 𝑓: 6.8e-7 (0 hom.)
• Consequence: TP53 NM_000546.6 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:7
• Conservation: PhyloP100: 7.91

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]

ACMG classification

Verdict is Pathogenic. Variant got 26 ACMG points.

• PS1: Transcript NM_000546.6 (TP53) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar as 568285
• PM1: In a hotspot region, there are 12 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 17 uncertain 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 ClinVar as [Likely_pathogenic]. Clinvar id is 141963.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
• 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	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: 1 AN: 251268 Hom.: 0 AF XY: 0.00000736 AC XY: 1 AN XY: 135852

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: 1 AN: 1461880 Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1 AN XY: 727240

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.: 33

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:7

Revision: criteria provided, multiple submitters, no conflicts

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: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.99
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
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	D
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	D
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	D
MutationTaster	Benign	1.0	D;D;D;D;D;D
PrimateAI	Uncertain	0.55	T
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	D
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

Other links and lift over

dbSNP: rs587782144; hg19: chr17-7578457; COSMIC: COSV52676395; COSMIC: COSV52676395;