ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.772G>A (p.Glu258Lys) (rs121912652)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000161071 SCV000211805 pathogenic not provided 2018-07-19 criteria provided, single submitter clinical testing This variant is denoted TP53 c.772G>A at the cDNA level, p.Glu258Lys (E258K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant was observed in an individual with early-onset breast cancer and family history meeting criteria for Li-Fraumeni syndrome (Malkin 1990) as well as in individuals with gastric and brain cancer (Masciari 2011, Huang 2018). Functional studies have consistently found TP53 Glu258Lys to severely impact transcriptional activation (Flaman 1998, Malcikova 2010, Monti 2011) and this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). In addition, Frebourg et al. (1992) demonstrated that this variant results in loss of cellular growth inhibition. TP53 Glu258Lys 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 currently available evidence, we consider TP53 Glu258Lys to be pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000161071 SCV000602278 pathogenic not provided 2016-09-23 criteria provided, single submitter clinical testing
Color Health, Inc RCV000772122 SCV000905196 pathogenic Hereditary cancer-predisposing syndrome 2021-01-14 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 258 in the DNA binding domain of the TP53 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that the mutant protein to be non-functional and exhibit dominant negative effect in transactivation assays (PMID: 12826609, 16492679, 20128691, 21343334) and in cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with Li-Fraumeni syndrome (PMID: 9667734, 10922393, 1978757, 21552135). This variant has been identified in 1/246228 chromosomes in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Invitae RCV000792895 SCV000932221 likely pathogenic Li-Fraumeni syndrome 2018-12-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 258 of the TP53 protein (p.Glu258Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs121912652, ExAC 0.001%). This variant has been observed in several families affected with Li-Fraumeni syndrome-associated tumors (PMID: 1978757, 21552135, 9667734, 10922393, Invitae), and an individual affected with glioblastoma multiforme (PMID: 29625052). ClinVar contains an entry for this variant (Variation ID: 12348). Experimental studies have shown that this missense change results in almost null TP53 DNA-binding and transactivation activity, and that it may act in a dominant-negative manner in decreasing TP53 wild-type activity in vitro (PMID: 12826609, 21343334, 20128691). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Ambry Genetics RCV000772122 SCV001189203 likely pathogenic Hereditary cancer-predisposing syndrome 2018-02-16 criteria provided, single submitter clinical testing The p.E258K variant (also known as c.772G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 772. The glutamic acid at codon 258 is replaced by lysine, an amino acid with similar properties. The p.E258K variant was first reported in a patient diagnosed with breast cancer at 34 whose tumor demonstrated loss of heterozygosity (LOH), and whose family met classic LFS criteria with a history of early onset sarcomas, and brain tumors (Malkin D et al. Science. 1990 Nov;250:1233-8). This variant has also been reported in a family with a strong history of gastric cancers (Masciari S et al. Genet. Med. 2011 Jul;13:651-7). Yeast based functional studies showed this alteration to have loss of transactivation capacity, and dominant negative effect (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9). Additional studies on this variant conducted in mammalian cells showed inability to suppress growth, and a protein binding profile indicative of a mutant protein conformation (Frebourg T et al. Proc. Natl. Acad. Sci. U.S.A., 1992 Jul;89:6413-7). 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.
OMIM RCV000013141 SCV000033388 pathogenic Li-Fraumeni syndrome 1 2020-08-27 no assertion criteria provided literature only
Mayo Clinic Laboratories, Mayo Clinic RCV000582699 SCV000692070 uncertain significance not specified no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785291 SCV000923859 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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