ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.538G>A (p.Glu180Lys) (rs879253911)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235571 SCV000292772 likely pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing This variant is denoted TP53 c.538G>A at the cDNA level, p.Glu180Lys (E180K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has been observed in two children with adrenocortical carcinoma, one of whom was noted to have a family history of Li-Fraumeni-spectrum cancers (Birch 1994, Wasserman 2015). On functional interrogation, this variant has demonstrated reduced protein stability, growth suppression, and apoptotic activities as well as reduced binding to and transactivation of typical p53 response elements (Boyle 1999, Campomenosi 2001, Monti 2002, Malcikova 2010, Schlereth 2010, Monti 2011, Follis 2014, Kotler 2018). Consistent with these findings, TP53 Glu180Lys is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Glu180Lys was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available information, we consider TP53 Glu180Lys to be a likely pathogenic variant.
Ambry Genetics RCV000492319 SCV000581143 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s),Structural Evidence
Invitae RCV000544036 SCV000629836 likely pathogenic Li-Fraumeni syndrome 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 180 of the TP53 protein (p.Glu180Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual with pediatric adrenocortical carcinoma from a family affected with Li-Fraumeni-like syndrome (PMID: 8118819, 17311302). In addition, it has been reported in an unrelated individual with pediatric adrenocortical carcinoma (PMID: 25584008). ClinVar contains an entry for this variant (Variation ID: 245711). Experimental studies have shown that this missense change leads to reduced TP53 transactivation activity on multiple promoters, loss of DNA binding, and loss of apoptotic activity through reduced DNA binding cooperativity (PMID: 12826609, 20128691, 20471942, 21343334, 24814347). 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.

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