17-7675086-A-G

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PS1PM1PM2PM5PP3_StrongPP5

The NM_000546.6(TP53):c.526T>C(p.Cys176Arg) 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. 13/22 in silico tools predict a damaging outcome for this variant. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another nucleotide change resulting in the same amino acid substitution has been previously reported as Likely pathogenic in ClinVar. Another variant affecting the same amino acid position, but resulting in a different missense (i.e. C176W) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 33)

Failed GnomAD Quality Control

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:4U:1

Conservation

PhyloP100: 9.32

Publications

181 publications found

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 Gene-Disease associations (from GenCC):

breast cancer
Inheritance: AD Classification: DEFINITIVE Submitted by: Ambry Genetics
Li-Fraumeni syndrome
Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Labcorp Genetics (formerly Invitae), G2P, ClinGen, Orphanet
Li-Fraumeni syndrome 1
Inheritance: AD Classification: DEFINITIVE, STRONG Submitted by: Ambry Genetics, Genomics England PanelApp
adrenocortical carcinoma, hereditary
Inheritance: AD Classification: STRONG Submitted by: Ambry Genetics
sarcoma
Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
bone marrow failure syndrome 5
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
colorectal cancer
Inheritance: AD Classification: MODERATE Submitted by: Ambry Genetics
choroid plexus carcinoma
Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet

TP53 links:

Genome browser will be placed here

ACMG classification

Classification was made for transcript

Our verdict: Pathogenic. The variant received 15 ACMG points.

PS1

Transcript NM_000546.6 (TP53) is affected with MISSENSE_VARIANT having same AA change as one Pathogenic present in ClinVar.

PM1

In a hotspot region, there are 35 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 32 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 chr17-7675084-G-C is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376572.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.994

PP5

Variant 17-7675086-A-G is Pathogenic according to our data. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573. Variant chr17-7675086-A-G is described in CliVar as Conflicting_classifications_of_pathogenicity. Clinvar id is 376573.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.526T>C	p.Cys176Arg	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3	P04637-1K7PPA8Q53GA5

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.526T>C	p.Cys176Arg	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152212

Hom.:

Cov.:

Gnomad AFR

AF:

0.00

Gnomad AMI

AF:

0.00

Gnomad AMR

AF:

0.00

Gnomad ASJ

AF:

0.00

Gnomad EAS

AF:

0.00

Gnomad SAS

AF:

0.00

Gnomad FIN

AF:

0.00

Gnomad MID

AF:

0.00

Gnomad NFE

AF:

0.00

Gnomad OTH

AF:

0.00

GnomAD4 exome

Cov.:

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

152212

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

74374

African (AFR)

AF:

0.00

AC:

AN:

41466

American (AMR)

AF:

0.00

AC:

AN:

15276

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

3468

East Asian (EAS)

AF:

0.00

AC:

AN:

5190

South Asian (SAS)

AF:

0.00

AC:

AN:

4836

European-Finnish (FIN)

AF:

0.00

AC:

AN:

10616

Middle Eastern (MID)

AF:

0.00

AC:

AN:

316

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

68044

Other (OTH)

AF:

0.00

AC:

AN:

2088

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:4Uncertain:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1

Pathogenic:1

Feb 14, 2024

Myriad Genetics, Inc.

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

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]. -

Breast neoplasm

Pathogenic:1

May 03, 2020

Genomic Research Center, Shahid Beheshti University of Medical Sciences

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Dec 21, 2017

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.C176R variant (also known as c.526T>C), located in coding exon 4 of the TP53 gene, results from a T to C substitution at nucleotide position 526. The cysteine at codon 176 is replaced by arginine, an amino acid with highly dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and a dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Brachmann RK et al. Proc. Natl. Acad. Sci. U.S.A., 1996 Apr;93:4091-5; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (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 is one of four residues necessary to bind the zinc molecule that stabilizes the beta sheet structure of the protein. Any mutation affecting these residues is predicted to prevent or destabilize zinc binding, destabilizing the structure and resulting in loss of function (Martin AC et al. Hum Mutat. 2002 Feb; 19(2):149-64). Another alteration at this same position (TP53 p.C176Y) has been identified in a patient with Li Fraumeni syndrome (Ambry internal data). This variant was not reported in population-based cohorts in the Genome Aggregation Database (gnomAD) (Lek M et al. Nature, 2016 08;536:285-91). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Ovarian neoplasm

Pathogenic:1

Dec 01, 2018

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

Significance:Likely pathogenic

Review Status:no assertion criteria provided

Collection Method:research

- -

Li-Fraumeni syndrome

Uncertain:1

Aug 17, 2023

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This missense change has been observed in individual(s) with colorectal and renal tumors (PMID: 26659639). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces cysteine, which is neutral and slightly polar, with arginine, which is basic and polar, at codon 176 of the TP53 protein (p.Cys176Arg). ClinVar contains an entry for this variant (Variation ID: 376573). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.59

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

(source)

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.88

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

Eigen

Pathogenic

0.96

Eigen_PC

Pathogenic

0.89

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.83

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

0.93

MutationAssessor

Pathogenic

3.3

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

PhyloP100

9.3

PrimateAI

Pathogenic

0.81

PROVEAN

Pathogenic

-12

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

REVEL

Pathogenic

0.94

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

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

0.97

MutPred

0.94

Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);.;.;.;.;.;.;.;Gain of disorder (P = 0.0134);.;Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);Gain of disorder (P = 0.0134);.;.;Gain of disorder (P = 0.0134);.;.;.;.;

MVP

0.98

MPC

2.2

ClinPred

1.0

GERP RS

5.6

PromoterAI

0.19

Neutral

(source)

Varity_R

1.0

gMVP

0.91

Mutation Taster

=0/100

disease causing (ClinVar)

(source)

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

You must be logged in to view publications. This limit was set because tens of millions (!) of queries from AI bots are generated daily.

Variant summary

Frequency

Consequence

Scores

Clinical Significance

Conservation

Publications

ACMG classification

Transcripts

RefSeq

Ensembl

Frequencies

ClinVar

Submissions by phenotype

Computational scores

Splicing

Publications

Other links and lift over