TP53 NM_000546.5:c.1066G>C, Gly356Arg

This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 356 of the TP53 protein (p.Gly356Arg). This variant is present in population databases (rs766786605, gnomAD 0.0009%). This missense change has been observed in individual(s) with breast cancer (PMID: 35534704). ClinVar contains an entry for this variant (Variation ID: 234059). Invitae Evidence Modeling incorporating data from in vitro experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is not expected to disrupt TP53 function with a negative predictive value of 97.5%. Experimental studies have shown that this missense change does not substantially affect TP53 function (PMID: 12826609, 30224644). 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.

Variant summary: TP53 c.1066G>C (p.Gly356Arg) results in a non-conservative amino acid change located in the p53, tetramerisation domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 245622 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The c.1066G>C variant has been reported in the literature, but this report does not provide strong evidence about an association of the variant with Li-Fraumeni Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.

This missense variant replaces glycine with arginine at codon 356 of the TP53 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). A functional study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (IARC database; PMID: 12826609). This variant has been observed in a tumor sample from an individual affected with triple-negative breast cancer (PMID: 24356096). This variant has been identified in 1/245622 chromosomes in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.

The TP53 c.1066G>C (p.Gly356Arg) variant has been reported in the published literature in individuals at risk for Li-Fraumeni syndrome (PMID: 28861920 (2017)) and an individual affected with breast cancer (PMID: 35534704 (2022)). This variant has also been observed in a reportedly healthy individual (PMID: 33471991 (2021), see also LOVD (http://databases.lovd.nl/shared)). Assessment of experimental evidence regarding the effect of this variant on protein function suggests it has no effect relevant to disease (PMIDs: 30224644 (2018), 12826609 (2003)). The frequency of this variant in the general population (Genome Aggregation Database, http://gnomad.broadinstitute.org) is uninformative in the assessment of its pathogenicity. Analysis of this variant using bioinformatics tools for the prediction of the effect of amino acid changes on protein structure and function yielded predictions that this variant is benign. Based on the available information, we are unable to determine the clinical significance of this variant.