rs767328513
Variant summary
Our verdict is Pathogenic. Variant got 11 ACMG points: 11P and 0B. PM1PM2PM5PP3_StrongPP5
The NM_000546.6(TP53):c.454C>T(p.Pro152Ser) 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 Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. P152L) has been classified as Pathogenic.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
Genome browser will be placed here
ACMG classification
Verdict is Pathogenic. Variant got 11 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
TP53 | NM_000546.6 | c.454C>T | p.Pro152Ser | missense_variant | 5/11 | ENST00000269305.9 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
TP53 | ENST00000269305.9 | c.454C>T | p.Pro152Ser | missense_variant | 5/11 | 1 | NM_000546.6 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 33
GnomAD3 exomes AF: 0.00000398 AC: 1AN: 251312Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135846
GnomAD4 exome Cov.: 35
GnomAD4 genome ? Cov.: 33
ClinVar
Submissions by phenotype
Glioma susceptibility 1 Pathogenic:1
Likely pathogenic, criteria provided, single submitter | clinical testing | Genetics and Molecular Pathology, SA Pathology | Mar 14, 2022 | Classified in accordance with ClinGen TP53 Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines Version 1.2 - |
Hereditary cancer-predisposing syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 11, 2024 | The p.P152S pathogenic mutation (also known as c.454C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 454. The proline at codon 152 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 non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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). Another alteration at the same codon, p.P152L (c.455C>T), has been reported in multiple individuals with personal and/or family history consistent with Li-Fraumeni (LF) or Li-Fraumeni-like (LFL) syndrome (Wagner J et al. J Natl Cancer Inst. 1994; 86(22):1701-1710; Masciari S et al. Genetics in Medicine. 2011; 13(7): 651-657; Wasserman JD et al. J. Clin. Oncol., 2015 Feb;33:602-9; Yurgelun MB et al. JAMA Oncol 2015 May; 1(2):214-21). 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 Uncertain:1
Uncertain significance, criteria provided, single submitter | clinical testing | Invitae | Nov 08, 2022 | ClinVar contains an entry for this variant (Variation ID: 482230). 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 performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is present in population databases (rs767328513, gnomAD 0.0009%). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 152 of the TP53 protein (p.Pro152Ser). - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at