rs28934571
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PM1PM2PP3_StrongPP5_Very_Strong
The NM_000546.6(TP53):c.747G>T(p.Arg249Ser) 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 (★★).
Frequency
Genomes: not found (cov: 31)
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
11
4
4
Clinical Significance
Conservation
PhyloP100: -1.47
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 16 ACMG points.
PM1
In a region_of_interest Interaction with AXIN1 (size 176) in uniprot entity P53_HUMAN there are 53 pathogenic changes around while only 3 benign (95%) in NM_000546.6
PM2
Very rare variant in population databases, with high coverage;
PP3
MetaRNN computational evidence supports a deleterious effect, 0.988
PP5
Variant 17-7674216-C-A is Pathogenic according to our data. Variant chr17-7674216-C-A is described in ClinVar as [Likely_pathogenic]. Clinvar id is 12352.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TP53 | NM_000546.6 | c.747G>T | p.Arg249Ser | missense_variant | 7/11 | ENST00000269305.9 | NP_000537.3 |
Ensembl
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Protein | Appris | UniProt |
|---|---|---|---|---|---|---|---|---|---|---|
| TP53 | ENST00000269305.9 | c.747G>T | p.Arg249Ser | missense_variant | 7/11 | 1 | NM_000546.6 | ENSP00000269305 | P1 |
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
31
GnomAD4 exome Cov.: 32
GnomAD4 exome
Cov.:
32
GnomAD4 genome
GnomAD4 genome
Cov.:
31
ClinVar
Significance: Pathogenic/Likely pathogenic
Submissions summary: Pathogenic:12
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | May 08, 2023 | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 249 of the TP53 protein (p.Arg249Ser). This variant is not present in population databases (gnomAD no frequency). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 9407971, 15982667, 16754663, 19913028, 20516128, 20538734, 22110706, 25131192). 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. ClinVar contains an entry for this variant (Variation ID: 12352). This missense change has been observed in individual(s) with Li-Fraumeni Syndrome (PMID: 15982667). It has also been observed to segregate with disease in related individuals. - |
| Pathogenic, criteria provided, single submitter | research | University of Washington Department of Laboratory Medicine, University of Washington | May 25, 2018 | The TP53 variant designated as NM_000546.5:c.747G>T (p.Arg249Ser) is classified as pathogenic. This variant has not been reported in public population databases. Cosegregation analysis of one observed family was performed using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and shows a likelihood ratio of 7.52 to 1 that this allele explains cancer in the family (Thompson et al, 2003, PMID:2900794). Computer software programs (SIFT, Polyphen-2, PROVEAN) predict that this variant is likely to have a damaging effect. Experimental functional studies provide evidence that this variant can lead to loss of function by disrupting protein structure (Gouas et al, 2010, PMID: 20538734; Lee et al, 2008, PMID: 18477611; Butler et al, 2005, PMID: 15982667; Joerger et al, 2005, PMID: 15703170; Chan et al, 2004, PMID:15060172; Kato et al, 2003, PMID: 12826609; Bullock et al, 1997, PMID: 9405613). Additionally, analysis of breast tumor in one member of the observed family shows loss of heterozygosity for the allele with this TP53 variant in breast tissue, which adds moderate evidence that this variant is pathogenic. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID:29300386) gives about 99% probability of pathogenicity, which is consistent with a classification of pathogenic. The combined results are consistent with a classification of pathogenic in the context of Li-Fraumeni syndrome. This variant is expected to alter TP53 function and increase risks related to Li-Fraumeni syndrome associated cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Aug 16, 2021 | This missense variant replaces arginine with serine at codon 249 of the TP53 protein. Codon 249 is a known mutational hotspot for somatic mutation in cancer (PMID: 15982667, 17311302, 19756158, 28412734, 33300245). Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant to be defective in yeast-based transcriptional transactivation assays, and human cell proliferation and growth suppression assays (PMID: 12826609, 29979965, 30224644). This variant has been reported germline in individuals affected with early onset breast cancer (PMID: 30374176; Color internal data) and is reported at high frequency as a somatic mutation in Aflatoxin B1- and Hepatitis B virus-related hepatocellular carcinoma (PMID: 20182602, 30508182, 30608603). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jul 27, 2022 | The p.R249S pathogenic mutation (also known as c.747G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 747. The arginine at codon 249 is replaced by serine, an amino acid with dissimilar 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.R249K (c.746G>A), has been detected in one child with adrenal cortical carcinoma (Ambry internal data). The p.R249S alteration was classified as pathogenic by one study that evaluated multiple lines of evidence, including population data, functional evidence, in silico prediction models, segregation with disease and clinical phenotype including tumor characteristics (Tsai GJ et al. Genet Med, 2019 06;21:1435-1442). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This alteration has also 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 variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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. - |
Ovarian neoplasm Pathogenic:2
| Likely pathogenic, no assertion criteria provided | research | German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Dec 01, 2018 | - - |
| Likely pathogenic, no assertion criteria provided | clinical testing | University Health Network, Princess Margaret Cancer Centre | Mar 19, 2021 | - - |
Li-Fraumeni syndrome 1 Pathogenic:1
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 16, 2024 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 8001119, 8843196, 12509279, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. - |
Adrenal cortex carcinoma Pathogenic:1
| Likely pathogenic, no assertion criteria provided | clinical testing | Key Laboratory of Carcinogenesis and Cancer Invasion, Central South University | - | - - |
Cervical cancer Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 02, 1992 | - - |
not provided Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Aug 14, 2024 | In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 17332323, 16861262, 9627118, 20538734, 19366907, 23200676, 19376640, 24489544, 21869931, 23836507, 21768053, 22675488, 14741214, 19834951, 18477611, 22759751, 21445056, 27698932, 1349102, 1849234, 8174105, 7935394, 20407015, 27346245, 17344317, 10321740, 8843196, 15781620, 32475984, 15982667, 34282142, 20212049, 30224644, 19913028, 34326862, 34273903, 29979965, 15510160, 30374176) - |
Hepatocellular carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | literature only | OMIM | May 02, 1992 | - - |
Squamous cell carcinoma of the head and neck Pathogenic:1
| Pathogenic, criteria provided, single submitter | case-control | Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo | - | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Pathogenic
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Benign
DANN
Uncertain
DEOGEN2
Pathogenic
D;D;.;.;.;.;T;T;.;D;.;.;.;.;.;.;D;.;.;.
Eigen
Benign
Eigen_PC
Benign
FATHMM_MKL
Benign
N
LIST_S2
Uncertain
D;D;D;D;D;D;D;D;.;.;.;D;D;.;D;D;D;D;T;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;D
MetaSVM
Pathogenic
D
MutationAssessor
Pathogenic
.;.;.;.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Uncertain
T
PROVEAN
Pathogenic
D;D;.;.;.;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D
REVEL
Pathogenic
Sift
Uncertain
D;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;D
Polyphen
D;.;.;.;.;.;.;.;.;D;.;D;D;D;.;.;D;.;.;.
Vest4
MutPred
Loss of stability (P = 0.0441);Loss of stability (P = 0.0441);.;.;.;.;.;.;.;Loss of stability (P = 0.0441);.;Loss of stability (P = 0.0441);Loss of stability (P = 0.0441);Loss of stability (P = 0.0441);.;.;Loss of stability (P = 0.0441);.;.;.;
MVP
MPC
0.40
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