17-7675148-G-T

Variant names:

Variant summary

Our verdict is Pathogenic. The variant received 16 ACMG points: 16P and 0B. PM1PM2PM5PP3_ModeratePP5_Very_Strong

The NM_000546.6(TP53):c.464C>A(p.Thr155Asn) variant causes a missense change involving the alteration of a non-conserved nucleotide. The variant was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Likely pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. T155P) has been classified as Likely pathogenic.

Frequency

Genomes: not found (cov: 33)

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:6

Conservation

PhyloP100: 1.20

Publications

88 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 16 ACMG points.

PM1

In a hotspot region, there are 41 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 43 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 chr17-7675149-T-G is described in ClinVar as Conflicting_classifications_of_pathogenicity. ClinVar VariationId is 2768025.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.932

PP5

Variant 17-7675148-G-T is Pathogenic according to our data. Variant chr17-7675148-G-T is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 406564.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
TP53	NM_000546.6 link	c.464C>A	p.Thr155Asn	missense_variant	Exon 5 of 11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 link	c.464C>A	p.Thr155Asn	missense_variant	Exon 5 of 11	1	NM_000546.6	ENSP00000269305.4

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461882

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727244

African (AFR)

AF:

0.00

AC:

AN:

33480

American (AMR)

AF:

0.00

AC:

AN:

44724

Ashkenazi Jewish (ASJ)

AF:

0.00

AC:

AN:

26136

East Asian (EAS)

AF:

0.00

AC:

AN:

39700

South Asian (SAS)

AF:

0.00

AC:

AN:

86256

European-Finnish (FIN)

AF:

0.00

AC:

AN:

53414

Middle Eastern (MID)

AF:

0.00

AC:

AN:

5768

European-Non Finnish (NFE)

AF:

0.00

AC:

AN:

1112008

Other (OTH)

AF:

0.00

AC:

AN:

60396

GnomAD4 genome

Cov.:

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:6

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Pathogenic:2

Jun 02, 2022

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Variant summary: TP53 c.464C>A (p.Thr155Asn) results in a non-conservative amino acid change located in the DNA-binding domain (IPR011615) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 251290 control chromosomes. In addition to being widely reported in a variety of somatic cancers, c.464C>A has been reported in the literature as a reportedly germline variant in settings of glioma and breast cancer and (example, Kyritsis_1994, Nandikolla_2017). At least one publication reports experimental evidence evaluating an impact on protein function (example, Kato_2003). The most pronounced variant effect results in non-functional outcome based on overall transcription activity (TA) on eight different promoters as measured in yeast assays. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 (Likely pathogenic, n=2; VUS, n=1). Based on the evidence outlined above, the variant was classified as likely pathogenic. -

Oct 27, 2024

Labcorp Genetics (formerly Invitae), Labcorp

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

This sequence change replaces threonine, which is neutral and polar, with asparagine, which is neutral and polar, at codon 155 of the TP53 protein (p.Thr155Asn). 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: 8308926, 28356770; internal data). ClinVar contains an entry for this variant (Variation ID: 406564). 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). For these reasons, this variant has been classified as Pathogenic. -

not provided

Pathogenic:2

Jan 25, 2022

GeneDx

Significance:Likely pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

Published functional studies demonstrate a damaging effect: non-functional transactivation and dominant negative effect (Monti 2011, Giacomelli 2018, Kotler 2018); Not observed at significant frequency in large population cohorts (gnomAD); Observed in individuals with TP53-related cancers (Kyritsis 1994, Nandikolla 2017); In silico analysis supports that this missense variant does not alter protein structure/function; This variant is associated with the following publications: (PMID: 29979965, 15510160, 26718964, 25149524, 15781632, 32850382, 30840781, 17606709, 21343334, 30224644, 28356770, 24113472, 8308926, 32321992, 30720243) -

Mar 15, 2025

Quest Diagnostics Nichols Institute San Juan Capistrano

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The TP53 c.464C>A (p.Thr155Asn) variant has been reported in the published literature in individuals with Li-Fraumeni syndrome (LFS) (PMID: 17606709 (2007)) and LFS-associated cancers, such as breast cancer (PMID: 28356770 (2017), Ambry internal patients), glioblastoma (PMID: 8308926 (1994)), and leukemia (PMID: 24113472 (2014)). In experimental studies done with yeast and human cell lines, this variant disrupts protein function by decreasing transactivation activity, stability, transcription, and double strand break repair (PMID: 12826609 (2003), 17606709 (2007), 21343334 (2011), 29979965 (2018), 30224644 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). 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, this variant is classified as pathogenic. -

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]. -

Hereditary cancer-predisposing syndrome

Pathogenic:1

Apr 13, 2022

Ambry Genetics

Significance:Pathogenic

Review Status:criteria provided, single submitter

Collection Method:clinical testing

The p.T155N pathogenic mutation (also known as c.464C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 464. The threonine at codon 155 is replaced by asparagine, an amino acid with similar properties. This alteration has been detected in several individuals meeting the revised Chompret criteria (Kyritsis A et al. J. Natl. Cancer Inst. 1994 Mar; 86(5):344-9; Nandikolla A et al. Breast Cancer (Dove Med Press) 2017; 9 207-215; Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have a loss of transactivation in yeast-based assays (Monti P et al. Mol. Cancer Res. 2011 Mar; 9(3):271-9; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Smardova J et al. Oncol. Rep. 2016 Mar;35:1859-67). Studies conducted in human cell lines indicate this alteration has dominant-negative activity and 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). The threonine at codon 155 is a target of phosphorylation, which may be an important regulatory step for maintaining appropriate levels of p53 protein in the cell (Bech-Otschir D et al. EMBO J. 2001 Apr; 20(7):1630-9). 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This amino acid position is poorly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.77

BayesDel_addAF

Uncertain

0.14

BayesDel_noAF

Uncertain

-0.040

CADD

Benign

(source)

DANN

Benign

0.78

DEOGEN2

Uncertain

0.67

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

Eigen

Benign

-1.0

Eigen_PC

Benign

-1.2

FATHMM_MKL

Benign

0.41

LIST_S2

Uncertain

0.96

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

M_CAP

Pathogenic

0.45

MetaRNN

Pathogenic

0.93

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

2.3

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

PhyloP100

1.2

PrimateAI

Benign

0.36

PROVEAN

Benign

-2.2

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

REVEL

Uncertain

0.55

Sift

Uncertain

0.0030

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

Sift4G

Uncertain

0.0090

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

Polyphen

0.95

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

Vest4

0.71

MutPred

0.89

Loss of phosphorylation at T155 (P = 0.0156);Loss of phosphorylation at T155 (P = 0.0156);.;.;.;.;Loss of phosphorylation at T155 (P = 0.0156);.;Loss of phosphorylation at T155 (P = 0.0156);Loss of phosphorylation at T155 (P = 0.0156);Loss of phosphorylation at T155 (P = 0.0156);.;.;Loss of phosphorylation at T155 (P = 0.0156);.;.;.;.;Loss of phosphorylation at T155 (P = 0.0156);

MVP

0.87

MPC

1.5

ClinPred

0.64

GERP RS

-0.47

PromoterAI

0.044

Neutral

(source)

Varity_R

0.79

gMVP

0.45

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

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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