Submissions for variant NM_000546.6(TP53):c.455C>T (p.Pro152Leu)

gnomAD frequency: 0.00001  dbSNP: rs587782705

Total submissions: 20

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
ClinGen TP53 Variant Curation Expert Panel, ClinGen	RCV000168122	SCV001142563	pathogenic	Li-Fraumeni syndrome	2024-08-05	reviewed by expert panel	curation	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).
Ambry Genetics	RCV000132156	SCV000187230	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-15	criteria provided, single submitter	clinical testing	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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000168122	SCV000218779	pathogenic	Li-Fraumeni syndrome	2024-12-22	criteria provided, single submitter	clinical testing	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). 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, 20128691, 21343334). For these reasons, this variant has been classified as Pathogenic.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000132156	SCV000266135	pathogenic	Hereditary cancer-predisposing syndrome	2015-11-20	criteria provided, single submitter	clinical testing
CSER _CC_NCGL, University of Washington	RCV000168122	SCV000700113	pathogenic	Li-Fraumeni syndrome	2016-10-01	criteria provided, single submitter	research	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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine	RCV000168122	SCV000710875	pathogenic	Li-Fraumeni syndrome	2017-10-19	criteria provided, single submitter	clinical testing	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).
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000677669	SCV000803809	pathogenic	Li-Fraumeni syndrome 1	2016-01-25	criteria provided, single submitter	clinical testing
Equipe Genetique des Anomalies du Developpement, Université de Bourgogne	RCV000755703	SCV000883137	pathogenic	Familial cancer of breast	2018-11-21	criteria provided, single submitter	clinical testing
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo	RCV001270267	SCV001450482	pathogenic	Squamous cell carcinoma of the head and neck		criteria provided, single submitter	case-control
Institute of Human Genetics, University of Leipzig Medical Center	RCV000677669	SCV004027732	pathogenic	Li-Fraumeni syndrome 1	2023-07-03	criteria provided, single submitter	clinical testing	Criteria applied: PS3,PS4,PM1,PM2_SUP,PP3
Baylor Genetics	RCV003462034	SCV004206215	pathogenic	Adrenocortical carcinoma, hereditary	2023-10-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000132156	SCV004360006	pathogenic	Hereditary cancer-predisposing syndrome	2023-03-06	criteria provided, single submitter	clinical testing	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.
All of Us Research Program, National Institutes of Health	RCV000168122	SCV004823807	pathogenic	Li-Fraumeni syndrome	2024-01-22	criteria provided, single submitter	clinical testing	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.
Myriad Genetics, Inc.	RCV000677669	SCV004933272	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-14	criteria provided, single submitter	clinical testing	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].
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000583667	SCV005090279	pathogenic	not provided	2025-03-04	criteria provided, single submitter	clinical testing
Clinical Genetics Laboratory, Skane University Hospital Lund	RCV000583667	SCV005198841	pathogenic	not provided	2022-05-27	criteria provided, single submitter	clinical testing
Mayo Clinic Laboratories, Mayo Clinic	RCV000583667	SCV000692088	pathogenic	not provided		no assertion criteria provided	clinical testing
Institute of Medical Sciences, Banaras Hindu University	RCV001255632	SCV001432168	pathogenic	Lip and oral cavity carcinoma	2019-04-30	no assertion criteria provided	research
BRCAlab, Lund University	RCV000132156	SCV002589026	pathogenic	Hereditary cancer-predisposing syndrome	2022-08-26	no assertion criteria provided	clinical testing
Clinical Genetics and Genomics, Karolinska University Hospital	RCV004797600	SCV005419141	pathogenic	TP53-related disorder	2024-10-01	no assertion criteria provided	clinical testing