ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.848G>A (p.Arg283His) (rs371409680)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000507738 SCV000605420 likely pathogenic not specified 2016-11-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000131388 SCV000186364 likely pathogenic Hereditary cancer-predisposing syndrome 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
CSER_CC_NCGL; University of Washington Medical Center RCV000148904 SCV000190650 uncertain significance Astrocytoma 2016-06-16 criteria provided, single submitter research Identified by sequencing as part of the NHLBI Sequencing Project (ESP; no phenotype data). Reported in a patient with astroctyoma (PMID 12019170). Identified in a 14 year old with adrenocortical carcinoma inherited from an unaffected father and in a 32 year old woman with a history of cardiac paraganglioma and maternal family history of breast cancer (personal communication with Chimene Kesserwan and Arielle Yorczyk-Swanholm).
Color RCV000131388 SCV000903096 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-18 criteria provided, single submitter clinical testing
GeneDx RCV000213060 SCV000211762 uncertain significance not provided 2018-08-15 criteria provided, single submitter clinical testing This variant is denoted TP53 c.848G>A at the cDNA level, p.Arg283His (R283H) at the protein level, and results in the change of an Arginine to a Histidine (CGC>CAC). This variant has been reported as a germline finding in an individual with an astrocytoma (Ishii 1999). Although this variant is reported having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003), multiple other studies have revealed contradictory results. With the exception of the BAX reporter, transactivation of typical p53 response elements has been found to be either normal or partially present across multiple studies (Crook 1998, Di Como 1998, Flaman 1998, Robert 2000, Campomenosi 2001, Gaiddon 2001, Maurici 2001, Fulci 2002, Monti 2002, Resnick 2003, Dearth 2007, Monti 2011). With respect to BAX, an important regulator of apoptotic activity, most, but not all, studies have revealed decreased transactivation of this specific response element. However, TP53 Arg283His has not been shown to impact apoptotic activity, and results from colony formation and growth suppression assays have also been comparable to wild type (Crook 1998, Fulci 2002, Kotler 2018). TP53 Arg283His was not observed at a significant allele frequency 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 conflicting functional evidence as well as a lack of individuals with histories suspicious for Li-Fraumeni syndrome in the published literature and our internal laboratory cases, we consider TP53 Arg283His to be a variant of uncertain significance.
Genetic Services Laboratory, University of Chicago RCV000457935 SCV000597520 likely pathogenic Li-Fraumeni syndrome 2017-04-10 criteria provided, single submitter clinical testing
Invitae RCV000457935 SCV000545319 uncertain significance Li-Fraumeni syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 283 of the TP53 protein (p.Arg283His). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs371409680, ExAC 0.03%). This variant has been reported in an individual affected with astrocytoma and glioblastoma (PMID: 12019170, 10557074). ClinVar contains an entry for this variant (Variation ID: 142324). Experimental studies have shown that this variant affects TP53 transactivation activity at variable levels between different promoters in yeast-based assays (PMID: 12826609, 17311302, 9627118, 16861262, 21343334, 9546439, 11429705, 12019170). An additional study demonstrates that this variant leads to TP53 mislocalization, but that the protein still retains some growth suppressive and apoptotic activity (PMID: 9525742). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213060 SCV000602281 likely pathogenic not provided 2016-10-12 criteria provided, single submitter clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.