ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.344A>G (p.His115Arg) (rs730881996)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000575197 SCV000676296 uncertain significance Hereditary cancer-predisposing syndrome 2016-06-21 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000161021 SCV000211740 uncertain significance not provided 2018-04-27 criteria provided, single submitter clinical testing This variant is denoted TP53 c.344A>G at the cDNA level, p.His115Arg (H115R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003) and has been shown to have reduced binding affinity for p21 as compared to wild type (Zupnick 2006). TP53 His115Arg was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function.? Based on currently available evidence, it is unclear whether TP53 His115Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000696891 SCV000825472 uncertain significance Li-Fraumeni syndrome 2018-02-08 criteria provided, single submitter clinical testing This sequence change replaces histidine with arginine at codon 115 of the TP53 protein (p.His115Arg). The histidine residue is weakly conserved and there is a small physicochemical difference between histidine and arginine. 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. ClinVar contains an entry for this variant (Variation ID: 182925). An experimental study has shown that this missense change does not affect the transcriptional transactivation activity of the TP53 protein using eight different promoter elements (PMID: 12826609). However, in an independent assay a reduced affinity for the p53 response element of the p21 promoter has been reported (PMID: 16687402). 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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