ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1120G>C (p.Gly374Arg) (rs587781858)

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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 RCV000217404 SCV000273745 likely benign Hereditary cancer-predisposing syndrome 2017-06-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Intact protein function observed in appropriate functional assay(s),In silico models in agreement (benign)
GeneDx RCV000235558 SCV000293250 uncertain significance not provided 2017-09-06 criteria provided, single submitter clinical testing This variant is denoted TP53 c.1120G>C at the cDNA level, p.Gly374Arg (G374R) at the protein level, and results in the change of a Glycine to an Arginine (GGT>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). TP53 Gly374Arg was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Glycine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Gly374Arg occurs at a position that is not conserved and is located in the C-terminal regulatory domain and a nuclear localization signal (Shaulsky 1990, Bode 2004, Pessoa 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether TP53 Gly374Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000529612 SCV000629775 uncertain significance Li-Fraumeni syndrome 2018-10-31 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 374 of the TP53 protein (p.Gly374Arg). The glycine residue is moderately conserved and there is a moderate physicochemical difference between glycine and arginine. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the ExAC database. This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 230269). An experimental study using yeast-based assays has shown that this missense change does not affect the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). 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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