ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1036G>A (p.Glu346Lys)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000801312 SCV000941085 uncertain significance Li-Fraumeni syndrome 2018-08-15 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 346 of the TP53 protein (p.Glu346Lys). The glutamic acid residue is moderately 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 not been reported in the literature in individuals with TP53-related disease. The Glu346 amino acid falls in the tetramerization domain of the TP53 protein, comprising amino acid residues 325-356 (PMID: 11420672). Experimental studies have shown that Glu346Lys forms less thermostable tetramers and binds with greater affinity to Glu343Lys than wild type TP53 (PMID: 12433927).  Another experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). The clinical significance of these findings in currently unknown. 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.

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