ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.451C>T (p.Pro151Ser) (rs28934874)

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Total submissions: 24
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000079203 SCV000111072 pathogenic not provided 2012-12-28 criteria provided, single submitter clinical testing
Ambry Genetics RCV000219702 SCV000272964 likely pathogenic Hereditary cancer-predisposing syndrome 2020-07-14 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 reported in over 100 somatic tumors, and five times as a germline alteration including one individual with early onset and multiple primary sarcomas and central nervous system malignancies (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum Mutat. 2007 Jun;28(6):622-9). 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). In addition, another alteration at this same location segregated with disease in all five affected individuals from a classic LFS kindred and was associated with loss of the wild-type TP53 in tumor DNA (Vahteristo P et al. Cancer Res. 2001; 61:5718-22). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000633355 SCV000754577 pathogenic Li-Fraumeni syndrome 2020-06-30 criteria provided, single submitter clinical testing This sequence change replaces proline with serine at codon 151 of the TP53 protein (p.Pro151Ser). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and serine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 7881428, 17606709, 25584008, 20522432), and at least one of them has been confirmed to be de novo (PMID: 7881428). ClinVar contains an entry for this variant (Variation ID: 12370). This variant is located within the DNA-binding domain of the TP53 protein (PMID: 12826609). Experimental studies have shown that this missense change disrupts the transcriptional activity of TP53 protein and reduces its function as a tumor suppressor (PMID: 20128691, 12826609, 21343334, 16861262, 10713666, 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
OMIM RCV000013169 SCV000033416 pathogenic Breast adenocarcinoma 1991-05-01 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440140 SCV000508949 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422996 SCV000508950 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433689 SCV000508951 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440887 SCV000508952 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421928 SCV000508953 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000432585 SCV000508954 likely pathogenic Adenoid cystic carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443020 SCV000508955 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426058 SCV000508956 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431507 SCV000508957 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443379 SCV000508958 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424996 SCV000508959 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435681 SCV000508960 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420199 SCV000508961 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427411 SCV000508962 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438074 SCV000508963 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420869 SCV000508964 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429847 SCV000508965 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785532 SCV000924104 likely pathogenic Neoplasm of ovary 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

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