rs587782705
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PS3PS4PM1PP3_ModeratePP4_ModeratePP1PM2_Supporting
This summary comes from the ClinGen Evidence Repository: The NM_000546.6: c.455C>T variant in TP53 is a missense variant predicted to cause substitution of proline by leucine at amino acid 152 (p.Pro152Leu). This variant has been reported in 14 unrelated probands/families meeting Classic or Revised Chompret criteria, and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 8.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs26014290, 15654278, 10486318, 25584008, 17308077, Internal lab contributors; SCV000218779.10, SCV000187230.8). The variant has been reported to segregate with LFS-associated cancers in 4 meioses in 2 families (PP1; PMID:10486318, Internal lab contributors SCV000187230.8). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID:34906512, Internal lab contributors SCV000187230.8). This variant has an allele frequency of 0.000001695 (2/1180036 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).. In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 28 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (PM1, ≥ 10 somatic occurrences, PMID:30311369). Computational predictor scores (BayesDel =0.558; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Very Strong, PP4_Moderate, PP1, PM2_Supporting, PS3, PM1, PP3_Moderate. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024). LINK:https://erepo.genome.network/evrepo/ui/classification/CA000204/MONDO:0018875/009
Frequency
Genomes: 𝑓 0.0000066 ( 0 hom., cov: 33)
Exomes 𝑓: 0.0000014 ( 0 hom. )
Consequence
TP53
NM_000546.6 missense
NM_000546.6 missense
Scores
12
5
2
Clinical Significance
Conservation
PhyloP100: 10.0
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.
PS3
For more information check the summary or visit ClinGen Evidence Repository.
PS4
For more information check the summary or visit ClinGen Evidence Repository.
PM1
For more information check the summary or visit ClinGen Evidence Repository.
PM2
For more information check the summary or visit ClinGen Evidence Repository.
PP1
For more information check the summary or visit ClinGen Evidence Repository.
PP3
For more information check the summary or visit ClinGen Evidence Repository.
PP4
For more information check the summary or visit ClinGen Evidence Repository.
Transcripts
RefSeq
| Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | Protein | UniProt |
|---|---|---|---|---|---|---|---|---|
| TP53 | NM_000546.6 | c.455C>T | p.Pro152Leu | 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 | c.455C>T | p.Pro152Leu | missense_variant | 5/11 | 1 | NM_000546.6 | ENSP00000269305 | P1 |
Frequencies
GnomAD3 genomes 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33
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GnomAD3 exomes AF: 0.00000796 AC: 2AN: 251274Hom.: 0 AF XY: 0.00 AC XY: 0AN XY: 135824
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GnomAD4 exome AF: 0.00000137 AC: 2AN: 1461862Hom.: 0 Cov.: 35 AF XY: 0.00000138 AC XY: 1AN XY: 727230
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GnomAD4 genome 0.00000657 AC: 1AN: 152184Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0AN XY: 74336
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ClinVar
Significance: Pathogenic
Submissions summary: Pathogenic:19Other:1
Revision: reviewed by expert panel
LINK: link
Submissions by phenotype
Li-Fraumeni syndrome Pathogenic:5
| Pathogenic, criteria provided, single submitter | research | CSER _CC_NCGL, University of Washington | Oct 01, 2016 | Found in patient having exome sequencing due to suspicion for hereditary colon cancer and/or polyps. Patient is a 60 year old female diagnosed with colon cancer at age 39 and a family history of colon polyps. This interpretation considers GERP score and allele frequency data, in addition to published reports of the variant in the literature, available at the time of review. - |
| Pathogenic, criteria provided, single submitter | clinical testing | All of Us Research Program, National Institutes of Health | Jan 22, 2024 | This missense variant replaces proline with leucine at codon 152 of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. Experimental functional studies have shown that this variant displays deficiency in transcriptional transactivation, DNA binding, and activity in a colony reduction assay (PMID: 12826609, 17606709, 20128691, 21343334, 25584008). This variant has been reported in individuals affected with cancers associated with Li Fraumeni-like syndrome, including individuals affected with adrenocortical carcinoma, breast cancer, colorectal cancer, gastric cancer and melanoma (PMID: 7966399, 10486318, 15654279, 17308077, 18511570, 21552135, 21934104, 25584008, 26014290, 26086041). It has been shown that this variant segregates with disease in 3 families (PMID: 7966399, 17308077, 21552135). This variant has been identified in 2/251274 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine | Oct 19, 2017 | The p.Pro152Leu variant in TP53 has been reported in at least 10 individuals wit h TP53-associated cancers and segregated with disease in at least 5 affected rel atives from 3 families (Varley 1999, Dickens 2005, Bougeard 2008, Tabori 2007, M asciari 2011, Yurgelun 2015, IARC TP53 database, http://p53.iarc.fr/, ClinVar, V ariation ID: 142766). It has also been identified in several unaffected adult re latives (Varley 1999, Dickens 2005, Yurgelun 2015), suggesting reduced penetranc e for this variant. In vitro functional studies provide evidence that the p.Pro1 52Leu variant may impact protein function by severely reducing its DNA-binding a ctivity (Malcikova 2010, Monti 2011). This variant has been identified in 1/1115 66 European and 1/9848 Ashkenazi Jewish chromosomes by the Genome Aggregation Da tabase (gnomAD, http://gnomad.broadinstitute.org; dbSNP rs587782705). In summary , this variant meets criteria to be classified as pathogenic for Li-Fraumeni syn drome in an autosomal dominant manner based upon multiple reports in affected in dividuals, segregation studies, low frequency in controls, and functional eviden ce. ACMG/AMP Criteria applied: PS4_Strong, PP1_Moderate, PM2, PS3_Supporting, PP 3 (Richards 2015). - |
| Pathogenic, reviewed by expert panel | curation | ClinGen TP53 Variant Curation Expert Panel, ClinGen | Aug 05, 2024 | The NM_000546.6: c.455C>T variant in TP53 is a missense variant predicted to cause substitution of proline by leucine at amino acid 152 (p.Pro152Leu). This variant has been reported in 14 unrelated probands/families meeting Classic or Revised Chompret criteria, and reported in 1 individual under the age of 40 diagnosed with a HER2+ breast cancer. Based on this evidence, this variant scores 8.5 total points meeting the TP53 VCEP phenotype scoring criteria of ≥ 8 points. (PS4_Very Strong; PMIDs26014290, 15654278, 10486318, 25584008, 17308077, Internal lab contributors; SCV000218779.10, SCV000187230.8). The variant has been reported to segregate with LFS-associated cancers in 4 meioses in 2 families (PP1; PMID: 10486318, Internal lab contributors SCV000187230.8). At least two individuals with this variant were found to have a variant allele fraction of 5-25%, which is a significant predictor of variant pathogenicity (PP4_Moderate, PMID: 34906512, Internal lab contributors SCV000187230.8). This variant has an allele frequency of 0.000001695 (2/1180036 alleles) in the European (non-Finnish) population in gnomAD v4.1.0 which is lower than the Clingen TP53 VCEP threshold (<0.00004) for PM2_Supporting, and therefore meets this criterion (PM2_Supporting).. In vitro assays performed in yeast and/or human cell lines showed non-functional transactivation and loss of growth suppression activity indicating that this variant impacts protein function (PS3; PMIDs: 12826609, 30224644, 29979965). This variant has 28 somatic occurrences for the same amino acid change in cancerhotspots.org (v2) sufficient to be defined as a mutational hotspot by the Clingen TP53 VCEP (PM1, ≥ 10 somatic occurrences, PMID: 30311369). Computational predictor scores (BayesDel =0.558; Align GVGD = Class C65) are above recommended thresholds (BayesDel > 0.16 and an Align GVGD Class of 65), evidence that correlates with impact to TP53 via protein change (PP3_Moderate). In summary, this variant meets the criteria to be classified as Pathogenic for Li Fraumeni Syndrome based on the ACMG/AMP criteria applied, as specified by the ClinGen TP53 VCEP: PS4_Very Strong, PP4_Moderate, PP1, PM2_Supporting, PS3, PM1, PP3_Moderate. (Bayesian Points: 20; VCEP specifications version 2.0; 7/24/2024). - |
| Pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Dec 06, 2023 | This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 152 of the TP53 protein (p.Pro152Leu). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 7966399, 17606709, 21552135, 21934104, 26086041). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 142766). 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, 20128691, 21343334). For these reasons, this variant has been classified as Pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:4
| Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Feb 15, 2022 | The p.P152L pathogenic mutation (also known as c.455C>T) is located in coding exon 4 of the TP53 gene. This mutation results from a C to T substitution at nucleotide position 455. The proline at codon 152 is replaced by a leucine, an amino acid with similar properties. This alteration 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; Ambry internal data). 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 are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). An additional study examined the functional significance of this alteration using protein microarray and found it results in significantly reduced DNA-binding activity (Malcikova J et al. Biol. Chem.;391:197-205). 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. - |
| Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Mar 06, 2023 | This missense variant replaces proline with leucine at codon 152 of the TP53 protein. 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 the mutant protein displays deficiency in transcriptional transactivation, DNA binding, and activity in a colony reduction assay (PMID: 12826609, 17606709, 20128691, 21343334, 25584008). This variant has been reported in individuals affected with cancers associated with Li Fraumeni-like syndrome, including individuals affected with adrenocortical carcinoma, breast cancer, colorectal cancer, gastric cancer and melanoma (PMID: 7966399, 10486318, 15654279, 17308077, 18511570, 21552135, 21934104, 25584008, 26014290, 26086041). It has been shown that this variant segregates with disease in 3 families (PMID: 7966399, 17308077, 21552135). This variant has been identified in 2/251274 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic. - |
| Pathogenic, criteria provided, single submitter | clinical testing | University of Washington Department of Laboratory Medicine, University of Washington | Nov 20, 2015 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | BRCAlab, Lund University | Aug 26, 2022 | - - |
Li-Fraumeni syndrome 1 Pathogenic:3
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Jan 25, 2016 | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Institute of Human Genetics, University of Leipzig Medical Center | Jul 03, 2023 | Criteria applied: PS3,PS4,PM1,PM2_SUP,PP3 - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Feb 14, 2024 | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 10206274, 25584008]. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 7966399, 10486318, 10922393, 15654279, 17308077]. - |
not provided Pathogenic:3
| Pathogenic, flagged submission | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
| Pathogenic, no assertion criteria provided | clinical testing | Mayo Clinic Laboratories, Mayo Clinic | - | - - |
| Pathogenic, criteria provided, single submitter | clinical testing | Clinical Genetics Laboratory, Skane University Hospital Lund | May 27, 2022 | - - |
Adrenocortical carcinoma, hereditary Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Oct 19, 2023 | - - |
Familial cancer of breast Pathogenic:1
| Pathogenic, criteria provided, single submitter | clinical testing | Equipe Genetique des Anomalies du Developpement, Université de Bourgogne | Nov 21, 2018 | - - |
Lip and oral cavity carcinoma Pathogenic:1
| Pathogenic, no assertion criteria provided | research | Institute of Medical Sciences, Banaras Hindu University | Apr 30, 2019 | - - |
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 | - | - - |
Neoplasm Other:1
| -, criteria provided, single submitter | clinical testing | Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Jul 31, 2024 | - - |
Computational scores
Source:
Name
Calibrated prediction
Score
Prediction
AlphaMissense
Uncertain
BayesDel_addAF
Pathogenic
D
BayesDel_noAF
Pathogenic
CADD
Uncertain
DANN
Uncertain
DEOGEN2
Uncertain
D;D;.;.;.;.;D;.;.;.;.;.;.;D;.;.;.;D;D
Eigen
Pathogenic
Eigen_PC
Pathogenic
FATHMM_MKL
Pathogenic
D
LIST_S2
Uncertain
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
Uncertain
.;.;.;.;.;.;M;.;M;M;M;.;.;M;.;.;.;.;.
MutationTaster
Benign
D;D;D;D;D;D
PrimateAI
Benign
T
PROVEAN
Pathogenic
D;D;.;.;.;.;D;.;.;D;D;.;.;D;.;.;D;D;D
REVEL
Pathogenic
Sift
Pathogenic
D;D;.;.;.;.;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;.;.
Polyphen
D;.;.;.;.;.;D;.;P;D;P;.;.;D;.;.;.;D;.
Vest4
MutPred
Loss of catalytic residue at P151 (P = 0.0116);Loss of catalytic residue at P151 (P = 0.0116);.;.;.;.;Loss of catalytic residue at P151 (P = 0.0116);.;Loss of catalytic residue at P151 (P = 0.0116);Loss of catalytic residue at P151 (P = 0.0116);Loss of catalytic residue at P151 (P = 0.0116);.;.;Loss of catalytic residue at P151 (P = 0.0116);.;.;.;.;Loss of catalytic residue at P151 (P = 0.0116);
MVP
MPC
1.6
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