ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.413C>A (p.Ala138Asp) (rs750600586)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000633392 SCV000754614 uncertain significance Li-Fraumeni syndrome 2017-12-28 criteria provided, single submitter clinical testing This sequence change replaces alanine with aspartic acid at codon 138 of the TP53 protein (p.Ala138Asp). The alanine residue is highly conserved and there is a moderate physicochemical difference between alanine and aspartic acid. 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. Experimental studies have shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 9472631, 12826609). A different missense substitution at this codon (p.Ala138Pro) has been reported to segregate with Li-Fraumeni syndrome-related cancers in one family (PMID: 9569035, 17567834), and to impair normal function of the TP53 protein in experimental studies (PMID: 21343334, 17606709, 15548685, 19958544, 12826609). This suggests that the alanine residue is critical for TP53 protein function and that other missense substitutions at this position may also be damaging. 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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