rs746601313

Variant summary

Our verdict is Likely benign. Variant got -3 ACMG points: 5P and 8B. PM1PM5PP3BP6_Very_Strong

The NM_000546.6(TP53):c.760A>G(p.Ile254Val) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.00000682 in 1,612,700 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 benign (★★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. I254N) has been classified as Likely pathogenic.

Frequency

Genomes: 𝑓 0.0000066 ( 0 hom., cov: 30)

Exomes 𝑓: 0.0000068 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Likely benign reviewed by expert panel U:6B:3

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:

Genome browser will be placed here

ACMG classification

Classification made for transcript

Verdict is Likely_benign. Variant got -3 ACMG points.

PM1

In a hotspot region, there are 14 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 4 benign, 15 uncertain in NM_000546.6

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7674202-A-T is described in ClinVar as [Likely_pathogenic]. Clinvar id is 856299.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.804

BP6

Variant 17-7674203-T-C is Benign according to our data. Variant chr17-7674203-T-C is described in ClinVar as [Likely_benign]. Clinvar id is 406605.Status of the report is reviewed_by_expert_panel, 3 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.760A>G	p.Ile254Val	missense_variant	7/11	ENST00000269305.9

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.760A>G	p.Ile254Val	missense_variant	7/11	1	NM_000546.6	P1	P04637-1

Frequencies

GnomAD3 genomes

AF:

0.00000659

AC:

AN:

151808

Hom.:

Cov.:

show subpopulations

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:

0.0000147

Gnomad OTH

AF:

0.00

GnomAD3 exomes

AF:

0.0000159

AC:

AN:

251476

Hom.:

AF XY:

0.0000221

AC XY:

AN XY:

135908

show subpopulations

Gnomad AFR exome

AF:

0.00

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:

0.0000352

Gnomad OTH exome

AF:

0.00

GnomAD4 exome

AF:

0.00000685

AC:

AN:

1460892

Hom.:

Cov.:

AF XY:

0.00000413

AC XY:

AN XY:

726838

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:

0.00000900

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

AF:

0.00000659

AC:

AN:

151808

Hom.:

Cov.:

AF XY:

0.0000135

AC XY:

AN XY:

74150

show subpopulations

Gnomad4 AFR

AF:

0.00

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:

0.0000147

Gnomad4 OTH

AF:

0.00

Alfa

AF:

0.0000740

Hom.:

Bravo

AF:

0.00000756

ExAC

AF:

0.00000824

AC:

EpiCase

AF:

0.0000545

EpiControl

AF:

0.00

ClinVar

Significance: Likely benign

Submissions summary: Uncertain:6Benign:3

Revision: reviewed by expert panel

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:2

Uncertain significance, criteria provided, single submitter	clinical testing	Invitae	Jan 11, 2024	This sequence change replaces isoleucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 254 of the TP53 protein (p.Ile254Val). This variant is present in population databases (rs746601313, gnomAD 0.003%). This missense change has been observed in individual(s) with TP53-related conditions (PMID: 21348412, 27242894, 28861920, 29769598, 32817165; Invitae). ClinVar contains an entry for this variant (Variation ID: 406605). 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 with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). 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. -
Uncertain significance, criteria provided, single submitter	clinical testing	All of Us Research Program, National Institutes of Health	Sep 17, 2023	This missense variant replaces isoleucine with valine at codon 254 of the TP53 protein. Computational prediction tool 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 shown that this variant does not impair TP53 protein function (PMID: 12826609, 29979965, 30224644). This variant is said to be reported in a family affected with Li-Fraumeni syndrome but detailed clinical findings were not provided for evaluation (PMID: 21348412). This variant has been reported in individuals affected with breast cancer (PMID: 33471991), non-small cell lung cancer (PMID: 27242894), and uveal melanoma (PMID: 29769598), as well as in control individuals unaffected with cancer (PMID: 28861920, 33471991). Other variants at this position have been classified as pathogenic (ClinVar Variation ID: 856299) suggesting the amino acid residue is important for function. This variant has been identified in 4/251476 individuals the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not provided

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	GeneDx	Jun 24, 2019	Not observed at a significant frequency in large population cohorts (Lek et al., 2016); This variant is associated with the following publications: (PMID: 21348412, 16596195, 10225439, 22634756, 25612911, 10811497, 14559903, 24663046, 23403321, 15370252, 25675526, 27242894, 25801821, 28975018, 27930734, 29979965, 28861920, 29769598, 30840781) -
Uncertain significance, criteria provided, single submitter	clinical testing	Quest Diagnostics Nichols Institute San Juan Capistrano	Dec 12, 2022	The frequency of this variant in the general population, 0.000035 (4/113752 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. In the published literature, the variant has been reported in families suspected of Li-Fraumeni Syndrome (LFS) (PMID: 21348412 (2010), 32817165 (2020)), in individuals with acute lymphocytic leukemia (ALL) (PMID: 23403321 (2013)), non-small cell lung cancer (NSCLC) (PMID: 27242894 (2016)), uveal melanoma (PMID: 29769598 (2018)), and pancreatic cancer (PMID: 35047863 (2022)). It has also been reported in a large breast cancer association study in affected and unaffected individuals (PMID: 33471991 (2021), https://databases.lovd.nl/shared/variants/TP53). Functional studies found this variant did not have an effect on TP53 protein function (PMID: 12826609 (2003), 29979965 (2018), 30224644 (2018)). Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is damaging. Based on the available information, we are unable to determine the clinical significance of this variant. -

Hereditary cancer-predisposing syndrome

Uncertain:1Benign:1

Likely benign, criteria provided, single submitter	clinical testing	Ambry Genetics	Jul 11, 2022	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	Color Diagnostics, LLC DBA Color Health	Apr 06, 2023	This missense variant replaces isoleucine with valine at codon 254 of the TP53 protein. Computational prediction tool 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 shown that this variant does not impair TP53 protein function (PMID: 12826609, 29979965, 30224644). This variant is said to be reported in a family affected with Li-Fraumeni syndrome but detailed clinical findings were not provided for evaluation (PMID: 21348412). This variant has been reported in individuals affected with breast cancer (PMID: 33471991), non-small cell lung cancer (PMID: 27242894), and uveal melanoma (PMID: 29769598), as well as in control individuals unaffected with cancer (PMID: 28861920, 33471991). Other variants at this position have been classified as pathogenic (ClinVar Variation ID: 856299) suggesting the amino acid residue is important for function. This variant has been identified in 4/251476 individuals the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. -

not specified

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Genetic Services Laboratory, University of Chicago

Oct 24, 2018

- -

Choroid plexus papilloma;C0235974:Carcinoma of pancreas;C0346153:Familial cancer of breast;C0585442:Bone osteosarcoma;C0699790:Carcinoma of colon;C1835398:Li-Fraumeni syndrome 1;C1859972:Adrenocortical carcinoma, hereditary;C2239176:Hepatocellular carcinoma;C2750850:Glioma susceptibility 1;C2931822:Nasopharyngeal carcinoma;C3553606:Basal cell carcinoma, susceptibility to, 7

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Oct 31, 2018

- -

Li-Fraumeni syndrome 1

Benign:1

Likely benign, reviewed by expert panel

curation

ClinGen TP53 Variant Curation Expert Panel, ClinGen

Aug 03, 2021

This variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show retained function according to Kato, et al. and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3; PMID: 12826609, 30224644). This variant has been observed in 7 60+ year old females without a cancer diagnosis (BS2_Supporting; Internal laboratory contributor). In summary, TP53 c.760A>G (p.Ile254Val) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PP3, BS3, BS2_Supporting. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Benign

0.19

BayesDel_addAF

Pathogenic

0.24

BayesDel_noAF

Pathogenic

0.17

Cadd

Benign

Dann

Uncertain

1.0

DEOGEN2

Benign

0.40

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

Eigen

Uncertain

0.34

Eigen_PC

Uncertain

0.36

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

M_CAP

Pathogenic

0.60

MetaRNN

Pathogenic

0.80

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

MetaSVM

Pathogenic

1.0

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.67

PROVEAN

Benign

-0.88

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

REVEL

Pathogenic

0.78

Sift

Pathogenic

0.0

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

Sift4G

Pathogenic

0.0

D;T;T;T;T;T;T;T;T;D;T;T;T;T;T;T;D;T;D;T

Polyphen

0.97

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

Vest4

0.73

MVP

0.91

MPC

0.26

ClinPred

0.82

GERP RS

4.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.69

gMVP

0.43

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