ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.524G>T (p.Arg175Leu) (rs28934578)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000161065 SCV000275440 likely pathogenic Hereditary cancer-predisposing syndrome 2015-04-28 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
Invitae RCV000810785 SCV000951018 uncertain significance Li-Fraumeni syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 175 of the TP53 protein (p.Arg175Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual affected with adrenocortical carcinoma (PMID: 16707427). ClinVar contains an entry for this variant (Variation ID: 182963). An experimental study in yeast has shown that this variant partially impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). Additionally, this variant has been reported to have conflicting data to determine the effect on TP53 protein function (PMID: 16707427, 16861262). This variant disrupts the p.Arg175 amino acid residue in TP53. Other variants that disrupt this residue (p.Arg175His, p.Arg175Gly) have been observed in many individuals and families affected with TP53-related disease (PMID: 11370630, 25927356, 8825920, 8164043, 21761402, 22006311), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. 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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