ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.604C>T (p.Arg202Cys) (rs587780072)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563913 SCV000664385 likely benign Hereditary cancer-predisposing syndrome 2017-08-17 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Intact protein function observed in appropriate functional assay(s),Other data supporting benign classification
Color RCV000563913 SCV000908790 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-04 criteria provided, single submitter clinical testing
GeneDx RCV000115729 SCV000149638 uncertain significance not provided 2016-07-12 criteria provided, single submitter clinical testing This variant is denoted TP53 c.604C>T at the cDNA level, p.Arg202Cys (R202C) at the protein level, and results in the change of an Arginine to a Cysteine (CGT>TGT). TP53 Arg202Cys has been identified as a germline variant in cis with another TP53 variant in an individual with a personal and family history of adrenal cortical carcinoma (Herrmann 2012). TP53 Arg202Cys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Arg202Cys occurs at a position that is not conserved and is located within the DNA binding domain (Bode 2004). 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 Arg202Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000473040 SCV000545281 uncertain significance Li-Fraumeni syndrome 2018-12-05 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 202 of the TP53 protein (p.Arg202Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs587780072, ExAC 0.009%). This variant has been reported in an individual affected with adrenocortical carcinoma (PMID: 22170717). ClinVar contains an entry for this variant (Variation ID: 127818). 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.

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