17-7673823-C-T

Position:

chr17-7673823-C-T

Variant summary

Our verdict is Pathogenic. Variant got 14 ACMG points: 14P and 0B. PM1PP3_StrongPP5_Very_Strong

The NM_000546.6(TP53):c.797G>A(p.Gly266Glu) variant causes a missense change involving the alteration of a conserved nucleotide. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★).

Frequency

Genomes: 𝑓 0.0 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:9U:1O:1

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Pathogenic. Variant got 14 ACMG points.

PM1

In a strand (size 10) in uniprot entity P53_HUMAN there are 6 pathogenic changes around while only 0 benign (100%) in NM_000546.6

PP3

MetaRNN computational evidence supports a deleterious effect, 0.99

PP5

Variant 17-7673823-C-T is Pathogenic according to our data. Variant chr17-7673823-C-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 161516.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.797G>A	p.Gly266Glu	missense_variant	8/11	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.797G>A	p.Gly266Glu	missense_variant	8/11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00

AC:

AN:

152024

Hom.:

Cov.:

FAILED QC

Gnomad AFR

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Gnomad AMI

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0.00

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0.00

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0.00

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0.00

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0.00

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

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AN:

1461062

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

726788

Gnomad4 AFR exome

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0.00

Gnomad4 AMR exome

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0.00

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0.00

GnomAD4 genome

Data not reliable, filtered out with message: AC0

AF:

0.00

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AN:

152024

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Cov.:

AF XY:

0.00

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AN XY:

74262

Gnomad4 AFR

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0.00

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0.00

Gnomad4 ASJ

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0.00

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0.00

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0.00

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0.00

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:9Uncertain:1Other:1

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Pathogenic:2

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Feb 22, 2023	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 266 of the TP53 protein (p.Gly266Glu). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 18511570, 24651015; external communication). ClinVar contains an entry for this variant (Variation ID: 161516). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 11429705, 12826609, 12917626, 17724467, 20505364, 29979965, 30224644). This variant disrupts the p.Gly266 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 16827139, 20407015, 27523101, 29979965, 30224644; externalcommunication). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Likely pathogenic, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Dec 18, 2023	This missense variant replaces glycine with glutamic acid at codon 266 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have reported this variant as defective in yeast based transcriptional activation assays, and human cell growth suppression and proliferation assays (PMID: 12826609, 29979965, 30224644). This variant has been reported in individuals affected with childhood-onset medulloblastoma (PMID: 22265402, 24651015), adrenocortical carcinoma (PMID: 26580448, 32371905), and in an individual with a personal and/or family history suggestive of Li Fraumeni syndrome (PMID: 18511570). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. -

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 20, 2024	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 29979965, 20505364]. This variant is expected to disrupt protein structure [Myriad internal data]. -

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	Nov 21, 2023	The p.G266E pathogenic mutation (also known as c.797G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 797. The glycine at codon 266 is replaced by glutamic acid, an amino acid with similar properties. This variant has been identified as a somatic mutation in tumors 91 times, and as a germline alteration in one individual with medulloblastoma (Petitjean A et al. IARC TP53 database [version R18, April 2016]. Hum. Mutat. 2007 Jun;28(6):622-9; Kool M et al. Cancer Cell. 2014 Mar; 25(3):393-405). This variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based functional studies (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. U.S.A. 2003 Jul 8;100(14):8424-9; Campomenosi P et al. Oncogene. 2001 Jun; 20(27):3573-9). 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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Cho Y et al. Science 1994 Jul;265(5170):346-55). 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. -

not provided

Pathogenic:1

Likely pathogenic, criteria provided, single submitter

clinical testing

GeneDx

Jan 07, 2019

This variant is denoted TP53 c.797G>A at the cDNA level, p.Gly266Glu (G266E) at the protein level, and results in the change of a Glycine to a Glutamic Acid (GGA>GAA). This variant has been observed in at least one individual with childhood-onset medulloblastoma and another with personal/family reportedly suggestive of Li-Fraumeni syndrome (Bougeard 2008, Rausch 2012). Functional studies have consistently found that TP53 Gly266Glu is not capable of transactivating typical p53 response elements, leads to a loss of growth suppression activity, and does not exhibit a dominant-negative effect (Campomenosi 2001, Monti 2002, Grochova 2008, Slovackova 2010, Kotler 2018). 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 Gly266Glu 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 the currently available information, we consider TP53 Gly266Glu to be a likely pathogenic variant. -

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

Likely pathogenic, criteria provided, single submitter

clinical testing

Mendelics

May 28, 2019

- -

Malignant tumor of prostate

Uncertain:1

Uncertain significance, no assertion criteria provided

literature only

Science for Life laboratory, Karolinska Institutet

- -

Neoplasm

Other:1

-, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital

Jul 31, 2024

- -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

1.0

BayesDel_addAF

Pathogenic

0.58

BayesDel_noAF

Pathogenic

0.60

CADD

Pathogenic

DANN

Uncertain

1.0

DEOGEN2

Pathogenic

0.86

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

Eigen

Pathogenic

0.89

Eigen_PC

Pathogenic

0.80

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.67

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

0.91

MutationAssessor

Pathogenic

3.3

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

PrimateAI

Uncertain

0.72

PROVEAN

Pathogenic

-7.3

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

REVEL

Pathogenic

0.97

Sift

Pathogenic

0.0

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

Polyphen

1.0

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

Vest4

0.97

MutPred

0.93

Gain of phosphorylation at S269 (P = 0.1321);.;.;.;.;.;.;.;Gain of phosphorylation at S269 (P = 0.1321);.;Gain of phosphorylation at S269 (P = 0.1321);Gain of phosphorylation at S269 (P = 0.1321);Gain of phosphorylation at S269 (P = 0.1321);.;.;Gain of phosphorylation at S269 (P = 0.1321);.;.;.;

MVP

0.99

MPC

0.43

ClinPred

1.0

GERP RS

5.1

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.98

gMVP

0.93

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