ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.986C>T (p.Thr329Ile)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000808332 SCV000948438 uncertain significance Li-Fraumeni syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces threonine with isoleucine at codon 329 of the TP53 protein (p.Thr329Ile). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported as a germline variant in the literature in individuals with TP53-related disease. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. The p.Thr329 amino acid falls in the tetramerization domain of the TP53 protein, comprising amino acid residues 325-356 (PMID: 20978130). However, experimental studies have shown that this missense change does not significantly affect the thermal stability, tetramer formation, or transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 20978130). 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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