chr17-7675157-G-C
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.455C>G(p.Pro152Arg) 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 Likely pathogenic (★★). Synonymous variant affecting the same amino acid position (i.e. P152P) has been classified as Benign.
Frequency
Consequence
NM_000546.6 missense
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes Cov.: 33
GnomAD4 exome Cov.: 35
GnomAD4 genome Cov.: 33
ClinVar
Submissions by phenotype
Hereditary cancer-predisposing syndrome Pathogenic:2
The p.P152R variant (also known as c.455C>G), located in coding exon 4 of the TP53 gene, results from a C to G substitution at nucleotide position 455. The proline at codon 152 is replaced by arginine, an amino acid with 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;100:8424-9). Additional studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387; Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8). To date this alteration has not been reported as germline in the literature, however, another alteration at this same amino acid position (p.P152L) has been reported in an individual with adrenocortical carcinoma prior to age 14, whose mother (also a carrier of the mutation) was subsequently diagnosed with breast cancer at the age of 46 (Wagner J et al. J Natl Cancer Inst. 1994; 86(22):1701-1710). In addition, this alteration has been observed in a family meeting Chompret criteria (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic. -
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Li-Fraumeni syndrome 1 Pathogenic:1
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Li-Fraumeni syndrome Pathogenic:1
This sequence change replaces proline, which is neutral and non-polar, with arginine, which is basic and polar, at codon 152 of the TP53 protein (p.Pro152Arg). 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 (Invitae). ClinVar contains an entry for this variant (Variation ID: 824998). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). This variant disrupts the p.Pro152 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7966399, 17606709, 20128691, 21343334). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. -
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at