ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.720T>G (p.Ser240Arg) (rs764342812)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000544531 SCV000629859 uncertain significance Li-Fraumeni syndrome 2017-04-10 criteria provided, single submitter clinical testing This sequence change replaces serine with arginine at codon 240 of the TP53 protein (p.Ser240Arg). The serine residue is highly conserved and there is a moderate physicochemical difference between serine and arginine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. In vitro studies in yeast using site-directed mutagenesis have shown that TP53 proteins with this missense change have partially functional transactivation activity (PMID: 12826609), and other studies suggest that this variant retains the ability to suppress cell growth and bind MDM2 (PMID: 12509279). This variant has been classified as a second-site suppressor mutation that potentially creates a novel DNA contact and rescues the effect of other pathogenic variants (PMID: 23863845, 17401432, 15037740). However, the clinical significance of these findings is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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