Submissions for variant NM_000546.6(TP53):c.451C>T (p.Pro151Ser)

dbSNP: rs28934874

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Eurofins Ntd Llc (ga)	RCV000079203	SCV000111072	pathogenic	not provided	2012-12-28	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000219702	SCV000272964	pathogenic	Hereditary cancer-predisposing syndrome	2024-11-12	criteria provided, single submitter	clinical testing	The p.P151S variant (also known as c.451C>T), located in coding exon 4 of the TP53 gene, results from a C to T substitution at nucleotide position 451. The proline at codon 151 is replaced by serine, an amino acid with similar properties. This alteration has been confirmed as de novo in a proband with a personal history of adrenocortical carcinoma diagnosed at 7 months, fibrosarcoma of the scalp diagnosed at age 4, and a right sided retroperitoneal rhabdomyosarcoma diagnosed at age 5 (Gutiérrez MI et al. Hum Mol Genet, 1994 Dec;3:2247-8). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (Shi XB et al. Prostate. 2002 Apr;51(1):59-72; 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(2):289-98; Monti P et al. Mol. Cancer Res. 2011 Mar; 9(3):271-9). Studies conducted in human cell lines indicate this alteration 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). A study examining DNA binding in p53 alterations reported that p.P151S exhibited significantly decreased binding compared to wild type p53 (Malcikova J et al. Biol. Chem. 2010 391(2-3):197-205). Another study conducted in tumor cell lines indicates that this alteration may confer resistance to apoptosis. This same group performed structural analysis and concluded that this variant is likely to result in significant conformational changes that are deleterious to the function of the protein (Xie TX et al. Laryngoscope 2013 Jun;123(6):1416-23). 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 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 amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000633355	SCV000754577	pathogenic	Li-Fraumeni syndrome	2024-09-26	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 151 of the TP53 protein (p.Pro151Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with Li-Fraumeni syndrome (PMID: 7881428, 17606709, 20522432, 25584008). In at least one individual the variant was observed to be de novo. ClinVar contains an entry for this variant (Variation ID: 12370). 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: 10713666, 12826609, 16861262, 20128691, 21343334, 23625637). For these reasons, this variant has been classified as Pathogenic.
Mendelics	RCV000633355	SCV000839120	pathogenic	Li-Fraumeni syndrome	2018-07-02	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV000219702	SCV002582395	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288487	SCV002583057	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Department of Clinical Genetics, Copenhagen University Hospital, Rigshospitalet	RCV000633355	SCV005685078	pathogenic	Li-Fraumeni syndrome	2025-01-10	criteria provided, single submitter	clinical testing	The following ACMG criteria was used: PM2_SUP; PS2; PS3; PP3_MOD; PM1
OMIM	RCV000013169	SCV000033416	pathogenic	Breast adenocarcinoma	1991-05-01	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785532	SCV000924104	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257523	SCV001434349	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation