17-7675139-C-G

Position:

• chr17-7675139-C-G

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1 PM2 PM5 PP3_Strong PP5_Very_Strong

The NM_000546.6(TP53):​c.473G>C​(p.Arg158Pro) variant causes a missense change involving the alteration of a conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. 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)
• 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]

TP53 (HGNC:):

ACMG classification

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, 0.995
• PP5: Variant 17-7675139-C-G is Pathogenic according to our data. Variant chr17-7675139-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 246118.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	c.473G>C	p.Arg158Pro	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	c.473G>C	p.Arg158Pro	missense_variant	5/11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD4 exome Cov.: 35

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	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 14, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. -

Hereditary cancer-predisposing syndrome Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Sep 17, 2024	The p.R158P pathogenic mutation (also known as c.473G>C), located in coding exon 4 of the TP53 gene, results from a G to C substitution at nucleotide position 473. The arginine at codon 158 is replaced by proline, an amino acid with dissimilar properties. This alteration has been reported in a Li Fraumeni syndrome family (Morgan JE et al. Hum Mutat, 2010 Apr;31:484-91). It has also been reported in a pediatric patient meeting Chompret criteria with a personal history of rhabdomyosarcoma and osteosarcoma (Penkert J et al. J Hematol Oncol, 2022 Aug;15:107). This alteration has also been reported in a patient with acute myeloid leukemia (Zuo Z et al. Leuk Res Rep, 2023 Aug;20:100385). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation. -
Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -

Li-Fraumeni syndrome Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Feb 17, 2022

This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 158 of the TP53 protein (p.Arg158Pro). This variant is not present in population databases (gnomAD no frequency). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 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: 246118). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (PMID: 20127978; Invitae). -

not provided Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Nov 13, 2018

This variant is denoted TP53 c.473G>C at the cDNA level, p.Arg158Pro (R158P) at the protein level, and results in the change of an Arginine to a Proline (CGC>CCC). This variant has been observed in at least one individual reported to have Li-Fraumeni syndrome (Morgan 2010). On functional interrogation, TP53 Arg158Pro has been shown to impact transactivation, growth suppression, and cause a dominant-negative effect (Brachmann 1996, Dearth 2007, Kotler 2018). Consistent with these results, this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Arg158Pro was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider TP53 Arg158Pro to be a likely pathogenic variant. -

Squamous cell carcinoma of the head and neck Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.57	D
BayesDel_noAF	Pathogenic	0.58
CADD	Uncertain	24
DANN	Uncertain	0.98
DEOGEN2	Pathogenic	0.88	D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen	Uncertain	0.44
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	0.78	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
MutationAssessor	Pathogenic	3.2	.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
PrimateAI	Uncertain	0.56	T
PROVEAN	Pathogenic	-6.8	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
REVEL	Pathogenic	0.92
Sift	Pathogenic	0.0	D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
Sift4G	Uncertain	0.0020	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		0.96
MutPred		0.98		Loss of catalytic residue at R158 (P = 0.0066);Loss of catalytic residue at R158 (P = 0.0066);.;.;.;.;Loss of catalytic residue at R158 (P = 0.0066);.;Loss of catalytic residue at R158 (P = 0.0066);Loss of catalytic residue at R158 (P = 0.0066);Loss of catalytic residue at R158 (P = 0.0066);.;.;Loss of catalytic residue at R158 (P = 0.0066);.;.;.;.;Loss of catalytic residue at R158 (P = 0.0066);
MVP		1.0
MPC		2.0
ClinPred		1.0	D
GERP RS		4.6
Varity_R		0.99
gMVP		0.96

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: COSV52678258; COSMIC: COSV52678258;