17-7676591-C-T

Variant summary

Our verdict is Uncertain significance. Variant got 2 ACMG points: 2P and 0B. PM2

The NM_000546.6(TP53):c.4G>A(p.Glu2Lys) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.00000248 in 1,613,792 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. E2G) has been classified as Uncertain significance.

Frequency

Genomes: 𝑓 0.000013 ( 0 hom., cov: 31)

Exomes 𝑓: 0.0000014 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5B:1

Conservation

PhyloP100: 1.87

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 Uncertain_significance. Variant got 2 ACMG points.

PM2

Very rare variant in population databases, with high coverage;

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.4G>A	p.Glu2Lys	missense_variant	2/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.4G>A	p.Glu2Lys	missense_variant	2/11	1	NM_000546.6	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.0000132

AC:

AN:

152060

Hom.:

Cov.:

show subpopulations

Gnomad AFR

AF:

0.0000483

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

GnomAD3 exomes

AF:

0.00000399

AC:

AN:

250510

Hom.:

AF XY:

0.00000737

AC XY:

AN XY:

135688

show subpopulations

Gnomad AFR exome

AF:

0.0000621

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:

0.00000137

AC:

AN:

1461732

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727148

show subpopulations

Gnomad4 AFR exome

AF:

0.00

Gnomad4 AMR exome

AF:

0.00

Gnomad4 ASJ exome

AF:

0.00

Gnomad4 EAS exome

AF:

0.0000252

Gnomad4 SAS exome

AF:

0.00

Gnomad4 FIN exome

AF:

0.00

Gnomad4 NFE exome

AF:

0.00

Gnomad4 OTH exome

AF:

0.0000166

GnomAD4 genome

AF:

0.0000132

AC:

AN:

152060

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74254

show subpopulations

Gnomad4 AFR

AF:

0.0000483

Gnomad4 AMR

AF:

0.00

Gnomad4 ASJ

AF:

0.00

Gnomad4 EAS

AF:

0.00

Gnomad4 SAS

AF:

0.00

Gnomad4 FIN

AF:

0.00

Gnomad4 NFE

AF:

0.00

Gnomad4 OTH

AF:

0.00

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:5Benign:1

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Hereditary cancer-predisposing syndrome

Uncertain:2Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Mar 17, 2023	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. -
Uncertain significance, criteria provided, single submitter	clinical testing	Genome-Nilou Lab	Jun 18, 2022	- -
Uncertain significance, criteria provided, single submitter	clinical testing	Color Diagnostics, LLC DBA Color Health	Jan 06, 2019	- -

Li-Fraumeni syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Dec 29, 2022

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 does not substantially affect TP53 function (PMID: 12826609). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 490172). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is present in population databases (rs769884991, gnomAD 0.007%). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 2 of the TP53 protein (p.Glu2Lys). -

Li-Fraumeni syndrome 1

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genome-Nilou Lab

Jun 18, 2022

- -

not provided

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

GeneDx

Jun 24, 2020

Not observed at a significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Reported in adult study participants unaffected with cancer (de Andrade 2017); Published functional studies suggest no damaging effect: functional transactivation (Kato 2003); This variant is associated with the following publications: (PMID: 28861920, 12826609) -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.15

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Pathogenic

0.15

Cadd

Uncertain

Dann

Pathogenic

1.0

DEOGEN2

Benign

0.057

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

Eigen

Benign

0.077

Eigen_PC

Benign

0.12

FATHMM_MKL

Uncertain

0.79

LIST_S2

Uncertain

0.95

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

M_CAP

Uncertain

0.23

MetaRNN

Uncertain

0.45

T;T;T;T;T;T;T;T;T;T;T;T

MetaSVM

Pathogenic

0.97

MutationTaster

Benign

0.57

N;N;N;N;N;N

PROVEAN

Benign

-0.64

N;N;N;.;N;N;N;.;N;N;.;N

REVEL

Uncertain

0.55

Sift

Uncertain

0.0020

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

Sift4G

Uncertain

0.0080

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

Polyphen

0.79

P;.;P;D;P;D;P;.;B;D;.;.

Vest4

0.40

MutPred

0.20

Gain of ubiquitination at E2 (P = 0.0042);Gain of ubiquitination at E2 (P = 0.0042);Gain of ubiquitination at E2 (P = 0.0042);Gain of ubiquitination at E2 (P = 0.0042);Gain of ubiquitination at E2 (P = 0.0042);Gain of ubiquitination at E2 (P = 0.0042);Gain of ubiquitination at E2 (P = 0.0042);Gain of ubiquitination at E2 (P = 0.0042);Gain of ubiquitination at E2 (P = 0.0042);Gain of ubiquitination at E2 (P = 0.0042);Gain of ubiquitination at E2 (P = 0.0042);Gain of ubiquitination at E2 (P = 0.0042);

MVP

0.86

MPC

1.2

ClinPred

0.58

GERP RS

4.2

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.16

gMVP

0.34

Splicing

Name

Calibrated prediction

Score

Prediction

SpliceAI score (max)

0.030

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