rs147002414

Positions:

Variant summary

Our verdict is Pathogenic. Variant got 10 ACMG points: 10P and 0B. PM1PM2PM5PP3_Strong

The ENST00000269305.9(TP53):c.529C>T(p.Pro177Ser) variant causes a missense change involving the alteration of a 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 Uncertain significance (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P177L) has been classified as Uncertain significance.

Frequency

Genomes: not found (cov: 33)

Exomes 𝑓: 0.0 ( 0 hom. )

Failed GnomAD Quality Control

Consequence

TP53
ENST00000269305.9 missense

Scores

Clinical Significance

Uncertain significance criteria provided, multiple submitters, no conflicts U:2

Conservation

PhyloP100: 10.0

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 Pathogenic. Variant got 10 ACMG points.

PM1

In a hotspot region, there are 10 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 5 benign, 12 uncertain in ENST00000269305.9

PM2

Very rare variant in population databases, with high coverage;

PM5

Other missense variant is known to change same aminoacid residue: Variant chr17-7675082-G-C is described in ClinVar as [Likely_pathogenic]. Clinvar id is 458547.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

PP3

MetaRNN computational evidence supports a deleterious effect, 0.987

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
TP53	NM_000546.6 linkuse as main transcript	c.529C>T	p.Pro177Ser	missense_variant	5/11	ENST00000269305.9	NP_000537.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
TP53	ENST00000269305.9 linkuse as main transcript	c.529C>T	p.Pro177Ser	missense_variant	5/11	1	NM_000546.6	ENSP00000269305	P1	P04637-1

Frequencies

GnomAD3 genomes

Cov.:

GnomAD4 exome

Data not reliable, filtered out with message: AC0

AF:

0.00

AC:

AN:

1461886

Hom.:

Cov.:

AF XY:

0.00

AC XY:

AN XY:

727242

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:

0.00

Gnomad4 OTH exome

AF:

0.00

GnomAD4 genome

Cov.:

ClinVar

Significance: Uncertain significance

Submissions summary: Uncertain:2

Revision: criteria provided, multiple submitters, no conflicts

LINK: link

Submissions by phenotype

Li-Fraumeni syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Labcorp Genetics (formerly Invitae), Labcorp

Nov 30, 2020

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. Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 646495). This variant is not present in population databases (ExAC no frequency). This sequence change replaces proline with serine at codon 177 of the TP53 protein (p.Pro177Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. -

Hereditary cancer-predisposing syndrome

Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Ambry Genetics

Feb 17, 2023

The p.P177S variant (also known as c.529C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 529. The proline at codon 177 is replaced by serine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration remains proficient 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 alteration is structurally deleterious (Ambry internal data; Brandt T et al. BMC Genomics, 2009 Dec;10:628; Shi Z et al. J Mol Biol, 2011 Oct;413:495-512; Sulak M et al. Elife, 2016 Sep;5:; Gomes AS et al. Int J Mol Sci, 2018 Apr;19:). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. -

Computational scores

Source: dbNSFP v4.3

Name

Calibrated prediction

Score

Prediction

AlphaMissense

Pathogenic

0.98

BayesDel_addAF

Pathogenic

0.41

BayesDel_noAF

Pathogenic

0.35

CADD

Pathogenic

DANN

Pathogenic

1.0

DEOGEN2

Uncertain

0.76

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

Eigen

Pathogenic

0.98

Eigen_PC

Pathogenic

0.93

FATHMM_MKL

Pathogenic

1.0

LIST_S2

Uncertain

0.88

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

M_CAP

Pathogenic

0.53

MetaRNN

Pathogenic

0.99

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

MetaSVM

Pathogenic

0.93

MutationAssessor

Uncertain

2.9

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

MutationTaster

Benign

1.0

D;D;D;D;D;D

PrimateAI

Uncertain

0.65

PROVEAN

Pathogenic

-7.7

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

REVEL

Pathogenic

0.88

Sift

Pathogenic

0.0

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

Sift4G

Uncertain

0.012

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

Polyphen

0.99

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

Vest4

0.78

MutPred

0.92

Gain of phosphorylation at P177 (P = 0.0305);Gain of phosphorylation at P177 (P = 0.0305);.;.;.;.;.;.;.;Gain of phosphorylation at P177 (P = 0.0305);.;Gain of phosphorylation at P177 (P = 0.0305);Gain of phosphorylation at P177 (P = 0.0305);Gain of phosphorylation at P177 (P = 0.0305);.;.;Gain of phosphorylation at P177 (P = 0.0305);.;.;.;.;

MVP

0.90

MPC

1.6

ClinPred

1.0

GERP RS

5.6

RBP_binding_hub_radar

0.0

RBP_regulation_power_radar

1.1

Varity_R

0.98

gMVP

0.49

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