ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.773A>C (p.Glu258Ala) (rs1060501201)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000551157 SCV000629868 uncertain significance Li-Fraumeni syndrome 2017-06-05 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 258 of the TP53 protein (p.Glu258Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with a TP53-related disease. Experimental studies have shown that this missense change impairs the transactivation function of the TP53 protein (PMID: 12826609). A different missense substitution at this codon (p.Glu258Lys) has been described as a severe deficiency allele (PMID: 21343334), and has been determined to be pathogenic in several Li-Fraumeni syndrome families (PMID: 17606709, 21552135, 1978757). This suggests that the glutamic acid residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. In summary, this variant has uncertain impact on TP53 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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