ClinVar Miner

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

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131388 SCV000186364 uncertain significance Hereditary cancer-predisposing syndrome 2020-06-15 criteria provided, single submitter clinical testing The p.R283H variant (also known as c.848G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 848. The arginine at codon 283 is replaced by histidine, an amino acid with highly similar properties. This alteration was identified in a 41 year-old male with astrocytoma (Fulci G et al. Cancer Res. 2002 May;62:2897-905). This alteration has been identified in one family with a history consistent with Li-Fraumeni-like syndrome; however, this alteration has also been detected numerous times in our laboratory in individuals with a personal and family history inconsistent with a diagnosis of Li Fraumeni syndrome (Ambry internal data). Transactivation studies conducted in yeast and mammalian cells have shown variable results, with the altered protein able to activate some, but not all, downstream targets (Fulci G et al. Cancer Res. 2002 May;62:2897-905; Campomenosi P et al. Oncogene. 2001 Jun;20:3573-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98; Crook T et al. Oncogene. 1998 Mar;16:1429-41; IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul;100:8424-9). This variant also has conflicting reports of intracellular localization, with one group showing nuclear localization in yeast (Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98), and another showing nuclear exclusion in a human lymphoma cell line (Crook T et al. Oncogene. 1998 Mar;16:1429-41). However, this alteration has been shown to be proficient at growth suppression in multiple mammalian cell lines (Crook T et al. Oncogene. 1998 Mar;16:1429-41; Fulci G et al. Cancer Res. 2002 May;62:2897-905; Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear, and we cannot rule out the possibility that it is a low penetrance risk allele.
CSER _CC_NCGL, University of Washington 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).
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.
Invitae RCV000457935 SCV000545319 uncertain significance Li-Fraumeni syndrome 2020-10-23 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). This variant has been reported to have conflicting or insufficient data to determine the effect on TP53 protein function (PMID: 12826609, 30224644, 29979965, 17311302, 9627118, 16861262, 21343334, 9546439, 11429705, 12019170, 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.
Genetic Services Laboratory, University of Chicago RCV000457935 SCV000597520 likely pathogenic Li-Fraumeni syndrome 2017-04-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213060 SCV000602281 likely pathogenic not provided 2016-10-12 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000507738 SCV000605420 uncertain significance Li-Fraumeni syndrome 1 2020-02-06 criteria provided, single submitter clinical testing The TP53 c.848G>A; p.Arg283His variant (rs371409680), is reported in the literature in individuals affected with an astrocytoma or a glioblastoma (Fulci 2002, Ishii 1999) and in an individual with breast cancer (Susswein 2016). This variant is reported as likely pathogenic/uncertain significance by multiple laboratories in ClinVar (Variation ID: 142324), and is found in the general population with an overall allele frequency of 0.004% (10/ 251,452 alleles) in the Genome Aggregation Database. The arginine at codon 283 is moderately conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Functional analyses of the variant protein show variable results, although many show decreased transactivation and a moderate dominant-negative effect (see link TP53MutLoad database, Campomenosi 2001, Crook 1998, Di Como 1998, Flaman 1998, Fulci 2002). Additionally, recent analyses of Genome Aggregation Database frequency compared to affected individuals do not reach a consensus as to the clinical significance (Evans 2019, Fortuno 2019, Soussi 2019). Therefore, due to conflicting results, the clinical significance of this variant is uncertain.
Color Health, Inc RCV000131388 SCV000903096 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-09 criteria provided, single submitter clinical testing

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