ClinVar Miner

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

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000772122 SCV000905196 likely pathogenic Hereditary cancer-predisposing syndrome 2018-05-03 criteria provided, single submitter clinical testing
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.
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785291 SCV000923859 likely pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
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.
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000582699 SCV000692070 uncertain significance not specified no assertion criteria provided clinical testing
OMIM RCV000013141 SCV000033388 pathogenic Li-Fraumeni syndrome 1 1990-11-30 no assertion criteria provided literature only
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000161071 SCV000602278 pathogenic not provided 2016-09-23 criteria provided, single submitter clinical testing

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