ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1066G>C (p.Gly356Arg) (rs766786605)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213405 SCV000278550 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-06 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000213405 SCV000691572 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-04 criteria provided, single submitter clinical testing
GeneDx RCV000481680 SCV000569810 uncertain significance not provided 2018-12-10 criteria provided, single submitter clinical testing This variant is denoted TP53 c.1066G>C at the cDNA level, p.Gly356Arg (G356R) at the protein level, and results in the change of a Glycine to an Arginine (GGG>CGG). This variant has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. 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 Gly356Arg was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Gly356Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781911 SCV000920315 uncertain significance not specified 2018-02-23 criteria provided, single submitter clinical testing 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.
Invitae RCV000471717 SCV000545298 uncertain significance Li-Fraumeni syndrome 2018-12-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with arginine at codon 356 of the TP53 protein (p.Gly356Arg). The glycine residue is weakly conserved and there is a moderate physicochemical difference between glycine and arginine. This variant is present in population databases (rs766786605, ExAC 0.002%). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 234059). An experimental study in yeast has shown that this variant does not impair 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.
True Health Diagnostics RCV000213405 SCV000788222 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-22 no assertion criteria provided clinical testing

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