17-7674953-T-C

Position:

chr17-7674953-T-C

Variant summary

Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong

The NM_000546.6(TP53):c.578A>G(p.His193Arg) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,886 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. H193L) 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:10

Conservation

PhyloP100: 8.02

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 region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) 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 chr17-7674953-T-A is described in Lovd as [Pathogenic].

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 17-7674953-T-C is Pathogenic according to our data. Variant chr17-7674953-T-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 184979.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 link	c.578A>G	p.His193Arg	missense_variant	6/11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.578A>G	p.His193Arg	missense_variant	6/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.84e-7

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

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:10

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	Genome-Nilou Lab	Jun 18, 2022	- -
Likely pathogenic, criteria provided, single submitter	clinical testing	Myriad Genetics, Inc.	Feb 15, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15221755, 20128691, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7887414, 28356770]. -

not provided

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Sep 01, 2020	The variant has been reported in individuals with Li-Fraumeni syndrome related cancers in the published literature (PMID: 29752822 (2018), 28724667 (2017), 25945745 (2015), 22265402 (2012), 17606709 (2007), 7887414 (1995)). Functional data indicates that this variant acts in a dominant negative manner and disrupts the transcriptional transactivation and DNA binding activity of the TP53 protein (PMID: 21343334 (2011), 20128691 (2010), 16861262 (2007), 12826609 (2003), 9627118 (1998)). Based on the available information, we predict that the variant is likely pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Dec 12, 2023	In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17606709, 9627118, 15280671, 7887414, 19367569, 20128691, 21343334, 26425688, 9546439, 16322298, 16861262, 11238194, 21190917, 1458490, 30816478, 25945745, 29752822, 28724667, 30720243, 30840781, 31105275, 32817165, 15161705, 22265402, 30076369, 30224644, 29979965, 15510160, 28356770, 12826609) -

Hereditary cancer-predisposing syndrome

Pathogenic:2

Likely pathogenic, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Ambry Genetics	Oct 14, 2024	The p.H193R pathogenic mutation (also known as c.578A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 578. The histidine at codon 193 is replaced by arginine, an amino acid with highly similar properties. This variant has previously been reported in an individual from a family meeting classic Li Fraumeni syndrome criteria, in an individual meeting Chompret criteria, and in several unrelated individuals with early onset Li-Fraumeni spectrum tumors (Frebourg T et al. Am. J. Hum. Genet. 1995 Mar; 56(3):608-15; Nandikolla AG et al. Breast Cancer (Dove Med Press), 2017 Mar;9:207-215; Fortes FP et al. Braz. J. Med. Biol. Res. 2015 Jul;48:610-5; Bouaoun L et al. IARC TP53 database [version R18, April 2016]. Hum. Mutat. 2016 Sep;37:865-76). This alteration has also been reported in multiple breast cancer cohorts (Sun J et al. Clin Cancer Res, 2017 Oct;23:6113-6119; Li JY et al. Int J Cancer, 2019 01;144:281-289; Dorling et al. N Engl J Med. 2021 02;384:428-439). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays, a dominant negative effect, and reduced DNA binding activity (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol Cancer Res. 2011 Mar;9(3):271-9; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98). 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. 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

Oct 02, 2024

This sequence change replaces histidine, which is basic and polar, with arginine, which is basic and polar, at codon 193 of the TP53 protein (p.His193Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome-associated tumors (PMID: 7887414, 22265402, 25945745, 28724667; internal data). ClinVar contains an entry for this variant (Variation ID: 184979). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 9627118, 12826609, 16861262, 20128691, 21343334). For these reasons, this variant has been classified as Pathogenic. -

Adrenocortical carcinoma, hereditary

Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Baylor Genetics

Aug 09, 2022

- -

Ovarian neoplasm

Pathogenic:1

Likely pathogenic, no assertion criteria provided

research

German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne

Dec 01, 2018

- -

Squamous cell carcinoma of the head and neck

Pathogenic:1

Pathogenic, criteria provided, single submitter

case-control

Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.55

BayesDel_noAF

Pathogenic

0.56

CADD

Uncertain

DANN

Uncertain

0.99

DEOGEN2

Pathogenic

0.88

D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.;D

Eigen

Uncertain

0.48

Eigen_PC

Uncertain

0.34

FATHMM_MKL

Pathogenic

0.99

LIST_S2

Uncertain

0.93

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

M_CAP

Pathogenic

0.72

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

1.0

MutationAssessor

Pathogenic

3.0

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

PrimateAI

Uncertain

0.77

PROVEAN

Pathogenic

-7.7

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

REVEL

Pathogenic

0.88

Sift

Uncertain

0.0070

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;D;D;D;.

Polyphen

1.0

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

Vest4

0.96

MutPred

0.99

Gain of disorder (P = 0.073);Gain of disorder (P = 0.073);.;.;.;.;.;.;.;Gain of disorder (P = 0.073);.;Gain of disorder (P = 0.073);Gain of disorder (P = 0.073);Gain of disorder (P = 0.073);.;.;Gain of disorder (P = 0.073);.;.;.;.;

MVP

1.0

MPC

1.8

ClinPred

1.0

GERP RS

4.3

Varity_R

0.99

gMVP

0.90

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

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