ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.833C>T (p.Pro278Leu) (rs876659802)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000214784 SCV000276644 pathogenic Hereditary cancer-predisposing syndrome 2019-08-27 criteria provided, single submitter clinical testing The p.P278L pathogenic mutation (also known as c.833C>T), located in coding exon 7 of the TP53 gene, results from a C to T substitution at nucleotide position 833. The proline at codon 278 is replaced by leucine, an amino acid with similar properties. This alteration was identified as a de novo alteration in a female patient with multiple primary tumors, including liposarcoma at 41, bilateral Paget's disease and breast cancer at 42 and 45, and two malignant histiocytomas at 48 and 49 (Speiser P, Br. J. Cancer. 1996 Jul; 74(2):269-73). Functional characterization has shown that this alteration has a loss of transactivation capacity, dominant negative characteristics, and a defect in DNA binding (Monti P et al. Mol. Cancer Res. 2011 Mar; 9(3):271-9; Malcikova et al. J Biol. Chem. 391(2-3):197-205; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Dearth LR et al. Carcinogenesis. 2007 Feb; 28(2):289-98). 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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Malecka KA et al.Oncogene. 2009 Jan; 28(3):325-33). In addition, other alterations at this same amino acid position have been associated with Li-Fraumeni syndrome (Güran S et al. Cancer Genet. Cytogenet. 2005 Jul; 160(2):164-8; Bougeard G et al. J. Med. Genet. 2001 Apr; 38(4):253-7). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV001042706 SCV001206406 uncertain significance Li-Fraumeni syndrome 2020-10-20 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 278 of the TP53 protein (p.Pro278Leu). The proline residue is highly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 8688334, 21761402). ClinVar contains an entry for this variant (Variation ID: 232497). This variant has been reported to affect TP53 protein function (PMID: 21343334, 20128691, 16861262, 12826609, 30224644, 29979965). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV001541668 SCV001759693 pathogenic not provided 2019-05-15 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek et al., 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 31105275, 30840781, 30720243, 11590071, 10949938, 10914716, 2263646, 17606709, 16861262, 20128691, 17646286, 8688334, 21761402, 14559903, 9572492, 21343334, 29979965)
Database of Curated Mutations (DoCM) RCV000417969 SCV000509047 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428205 SCV000509048 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434963 SCV000509049 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419043 SCV000509050 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429345 SCV000509051 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439555 SCV000509052 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421915 SCV000509053 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430442 SCV000509054 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440687 SCV000509055 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423023 SCV000509056 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433311 SCV000509057 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000443824 SCV000509058 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000424153 SCV000509059 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785311 SCV000923879 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Institute of Medical Sciences, Banaras Hindu University RCV001374441 SCV001571404 pathogenic Gallbladder cancer 2020-10-30 no assertion criteria provided research

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