ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.670G>A (p.Glu224Lys)

dbSNP: rs1555525707
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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000573879 SCV000664444 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-18 criteria provided, single submitter clinical testing The p.E224K variant (also known as c.670G>A), located in coding exon 5 of the TP53 gene, results from a G to A substitution at nucleotide position 670. The glutamic acid at codon 224 is replaced by lysine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have decreased transactivation capacity compared to wild type, but no dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Oncogene, 2002 Mar;21:1641-8).This amino acid position is highly conserved through mammals but not in all available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV001858144 SCV002161573 uncertain significance Li-Fraumeni syndrome 2021-11-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 224 of the TP53 protein (p.Glu224Lys). Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 29979965, 30224644). 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). ClinVar contains an entry for this variant (Variation ID: 480767). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency).
Genome-Nilou Lab RCV000573879 SCV002582030 uncertain significance Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002289800 SCV002582518 uncertain significance Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Baylor Genetics RCV004569135 SCV005054347 uncertain significance Adrenocortical carcinoma, hereditary 2023-12-11 criteria provided, single submitter clinical testing

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