rs745425759

Variant names:

Your query was ambiguous. Multiple possible variants found:

Variant summary

Our verdict is Likely pathogenic. The variant received 7 ACMG points: 7P and 0B. PM1PM2PM5PP5

The NM_000546.6(TP53):c.776A>T(p.Asp259Val) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000686 in 1,458,346 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. D259A) has been classified as Pathogenic.

Frequency

Genomes: not found (cov: 31)

Exomes 𝑓: 6.9e-7 ( 0 hom. )

Consequence

TP53
NM_000546.6 missense

Scores

Clinical Significance

Conflicting classifications of pathogenicity criteria provided, conflicting classifications P:2U:4

Conservation

PhyloP100: 3.21

Publications

77 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: Likely_pathogenic. The variant received 7 ACMG points.

PM1

In a hotspot region, there are 35 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 7 benign, 29 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 chr17-7674187-T-G is described in ClinVar as Pathogenic. ClinVar VariationId is 2671888.Status of the report is no_assertion_criteria_provided, 0 stars.

PP5

Variant 17-7674187-T-A is Pathogenic according to our data. Variant chr17-7674187-T-A is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 485034.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.776A>T	p.Asp259Val	missense_variant	Exon 7 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.776A>T	p.Asp259Val	missense_variant	Exon 7 of 11	1	NM_000546.6	ENSP00000269305.4		P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

AF:

6.86e-7

AC:

AN:

1458346

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

725752

show subpopulations

⚠️ The allele balance in gnomAD version 4 Exomes is significantly skewed from the expected value of 0.5.

African (AFR)

AF:

0.00

AC:

AN:

33420

American (AMR)

AF:

0.00

AC:

AN:

44722

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26110

East Asian (EAS)

AF:

0.00

AC:

AN:

39682

South Asian (SAS)

AF:

0.00

AC:

AN:

86202

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5756

European-Non Finnish (NFE)

AF:

9.02e-7

AC:

AN:

1108762

Other (OTH)

AF:

0.00

AC:

AN:

60278

⚠️ The allele balance in gnomAD4 Exomes is highly skewed from 0.5 (p-value = 0.000000), which strongly suggests a high chance of mosaicism in these individuals.

Allele Balance Distribution

Red line indicates average allele balance

Average allele balance: 0.225

Heterozygous variant carriers

0.00

0.20

0.40

0.60

0.80

0.95

Allele balance

GnomAD4 genome

Cov.:

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Pathogenic:2Uncertain:4

Revision: criteria provided, conflicting classifications

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome 1

Uncertain:3

Apr 11, 2023

Myriad Genetics, Inc.

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk. -

May 02, 2018

Counsyl

Significance:Uncertain significance

Review Status:no assertion criteria provided

Collection Method:clinical testing

This submission and the accompanying classification are no longer maintained by the submitter. For more information on current observations and classification, please contact variantquestions@myriad.com. -

Jun 18, 2022

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Hereditary cancer-predisposing syndrome

Pathogenic:1Uncertain:1

Jun 18, 2022

Genome-Nilou Lab

Significance:Uncertain significance

Review Status:criteria provided, single submitter

Collection Method:clinical testing

- -

Jan 12, 2021

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.D259V pathogenic mutation (also known as c.776A>T), located in coding exon 6 of the TP53 gene, results from an A to T substitution at nucleotide position 776. The aspartic acid at codon 259 is replaced by valine, 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 in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9, Maurici D et al. Oncogene, 2001 Jun;20:3533-40; Campomenosi P et al. Oncogene, 2001 Jun;20:3573-9; Monti P et al. Oncogene, 2003 Aug;22:5252-60; Jordan JJ et al. Mol. Cancer Res., 2010 May;8:701-16). 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 amino acid position is highly conserved through mammals but not in all 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

Sep 05, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces aspartic acid, which is acidic and polar, with valine, which is neutral and non-polar, at codon 259 of the TP53 protein (p.Asp259Val). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of Li-Fraumeni syndrome (internal data). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 485034). 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: 12826609, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.95

BayesDel_addAF

Pathogenic

0.40

BayesDel_noAF

Pathogenic

0.33

CADD

Uncertain

(source)

DANN

Uncertain

0.99

DEOGEN2

Uncertain

0.49

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

Eigen

Uncertain

0.30

Eigen_PC

Uncertain

0.26

FATHMM_MKL

Uncertain

0.81

LIST_S2

Pathogenic

0.99

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

M_CAP

Pathogenic

0.91

MetaRNN

Uncertain

0.69

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

MetaSVM

Pathogenic

1.1

MutationAssessor

Uncertain

2.6

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

PhyloP100

3.2

PrimateAI

Uncertain

0.57

PROVEAN

Benign

-0.16

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

REVEL

Pathogenic

0.74

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.0020

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

Polyphen

0.96

P;.;.;.;.;.;.;.;.;P;.;P;P;P;.;.;P;.;.;.

Vest4

0.54

MutPred

0.57

Loss of disorder (P = 0.0433);Loss of disorder (P = 0.0433);.;.;.;.;.;.;.;Loss of disorder (P = 0.0433);.;Loss of disorder (P = 0.0433);Loss of disorder (P = 0.0433);Loss of disorder (P = 0.0433);.;.;Loss of disorder (P = 0.0433);.;.;.;

MVP

0.97

MPC

0.45

ClinPred

0.96

GERP RS

4.5

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.7

Varity_R

0.81

gMVP

0.62

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

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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