Submissions for variant NM_000546.6(TP53):c.451C>A (p.Pro151Thr)

dbSNP: rs28934874

Total submissions: 25

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130617	SCV000185493	pathogenic	Hereditary cancer-predisposing syndrome	2020-11-12	criteria provided, single submitter	clinical testing	The p.P151T pathogenic mutation (also known as c.451C>A), located in coding exon 4 of the TP53 gene, results from a C to A substitution at nucleotide position 451. The proline at codon 151 is replaced by threonine, an amino acid with highly similar properties. This mutation has been reported in several families meeting clinical criteria for Li-Fraumeni Syndrome (LFS) (Vahteristo P et al. Cancer Res. 2001; 61:5718-22; Ambry internal data). This variant was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet. Med. 2015 Aug;17:630-8). 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). This variant was not reported in population-based 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.
GeneDx	RCV000520731	SCV000617735	likely pathogenic	not provided	2018-08-24	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.451C>A at the cDNA level, p.Pro151Thr (P151T) at the protein level, and results in the change of a Proline to a Threonine (CCC>ACC). This variant has been observed in two individuals with early-onset breast cancer, one of whom had a family history of sarcoma and adrenocortical carcinoma (Vahteristo 2001, Maxwell 2015). Although this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003), and Monti et al. (2011) also found a significant reduction in transactivation activity, this variant was not found to cause a dominant-negative effect and only had a slight impact on growth suppression (Monti 2011, Kotler 2018). TP53 Pro151Thr was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on the currently available evidence, we consider TP53 Pro151Thr to be a likely pathogenic variant.
Invitae	RCV000691152	SCV000818896	pathogenic	Li-Fraumeni syndrome	2023-10-08	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 151 of the TP53 protein (p.Pro151Thr). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with early-onset breast cancer and TP53-related disease (PMID: 11479205, 25503501). ClinVar contains an entry for this variant (Variation ID: 12369). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965, 30224644). This variant disrupts the p.Pro151 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7881428, 10713666, 12826609, 16861262, 20128691, 20522432, 21343334, 23625637). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
Genome-Nilou Lab	RCV000130617	SCV002582396	likely pathogenic	Hereditary cancer-predisposing syndrome	2022-06-18	criteria provided, single submitter	clinical testing
Genome-Nilou Lab	RCV002288486	SCV002583058	likely pathogenic	Li-Fraumeni syndrome 1	2022-06-18	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV000520731	SCV004026691	pathogenic	not provided	2023-08-15	criteria provided, single submitter	clinical testing
OMIM	RCV000013168	SCV000033415	pathogenic	Breast adenocarcinoma	1993-07-01	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437544	SCV000508983	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418145	SCV000508984	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428384	SCV000508985	likely pathogenic	Adenoid cystic carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435159	SCV000508986	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417493	SCV000508987	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429500	SCV000508988	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439740	SCV000508989	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422094	SCV000508990	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428836	SCV000508991	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440812	SCV000508992	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423161	SCV000508993	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433405	SCV000508994	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443817	SCV000508995	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424222	SCV000508996	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434485	SCV000508997	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442802	SCV000508998	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425139	SCV000508999	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV001257524	SCV001434350	pathogenic	Rhabdomyosarcoma	2020-09-01	no assertion criteria provided	provider interpretation