chr17-7673781-C-G
Position:
Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PM1PM2PM5PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.839G>C(p.Arg280Thr) 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 (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. R280K) has been classified as Pathogenic.
Frequency
Genomes: not found (cov: 31)
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
16
2
1
Clinical Significance
Conservation
PhyloP100: 7.91
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]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PM1
In a region_of_interest Interaction with DNA (size 7) in uniprot entity P53_HUMAN there are 7 pathogenic changes around while only 0 benign (100%) 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 chr17-7673781-C-T is described in Lovd as [Pathogenic].
PP3
MetaRNN computational evidence supports a deleterious effect, 0.97
PP5
Variant 17-7673781-C-G is Pathogenic according to our data. Variant chr17-7673781-C-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12368.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 33
GnomAD4 exome
Cov.:
33
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:6
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 20, 2024 | 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]. - |
Li-Fraumeni syndrome Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Aug 27, 2024 | This sequence change replaces arginine, which is basic and polar, with threonine, which is neutral and polar, at codon 280 of the TP53 protein (p.Arg280Thr). 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 (PMID: 25927356, 28135145; internal data). ClinVar contains an entry for this variant (Variation ID: 12368). 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, 22999923, 29979965, 30224644). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
Malignant tumor of urinary bladder Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Laboratory of Urology, Hospital Clinic de Barcelona | - | - - |
Hereditary cancer-predisposing syndrome Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 10, 2021 | The p.R280T pathogenic mutation (also known as c.839G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 839. The arginine at codon 280 is replaced by threonine, an amino acid with similar properties. This alteration has been reported as a somatic mutation 108 times in various tumors by the IARC TP53 database (Bouaoun L et al. IARC TP53 database [version 20, July 2019]. Hum. Mutat. 2016 Sep;37:865-76). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation and dominant negative activity in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9; Dearth LR et al. Carcinogenesis, 2007 Feb;28:289-98). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect 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). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. - |
Acute myeloid leukemia Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Ayesha Lab, University of the Punjab | - | - - |
Nasopharyngeal carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | Jul 15, 1992 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Pathogenic
DANN
Uncertain
DEOGEN2
Pathogenic
D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Pathogenic
D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;D;D
M_CAP
Pathogenic
D
MetaRNN
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL
Pathogenic
Sift
Pathogenic
D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
Sift4G
Pathogenic
D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D;D
Polyphen
1.0, 1.0
.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4
MutPred
Gain of phosphorylation at R280 (P = 0.0113);.;.;.;.;.;.;.;Gain of phosphorylation at R280 (P = 0.0113);.;Gain of phosphorylation at R280 (P = 0.0113);Gain of phosphorylation at R280 (P = 0.0113);Gain of phosphorylation at R280 (P = 0.0113);.;.;Gain of phosphorylation at R280 (P = 0.0113);.;.;.;
MVP
MPC
0.43
ClinPred
D
GERP RS
RBP_binding_hub_radar
RBP_regulation_power_radar
Varity_R
gMVP
Splicing
Name
Calibrated prediction
Score
Prediction
SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at