ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.685T>C (p.Cys229Arg) (rs1064794312)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000482930 SCV000568760 uncertain significance not provided 2016-10-27 criteria provided, single submitter clinical testing This variant is denoted TP53 c.685T>C at the cDNA level, p.Cys229Arg (C229R) at the protein level, and results in the change of a Cysteine to an Arginine (TGT>CGT). This variant has been observed in at least two unrelated individuals of French Canadian ancestry with early-onset breast cancer, as well three unrelated individuals diagnosed with adrenocortical carcinoma under the age of 20 (Arcand 2015, Wasserman 2015). While Wasserman et al. (2015) found TP53 Cys229Arg to increase transactivation levels in comparison to wild-type, they also demonstrated it to reduce colony formation by 50%. In addition, this variant is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Cys229Arg 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 Cysteine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Cys229Arg occurs at a position that is not conserved and is located in the DNA binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently conflicting evidence, it is unclear whether TP53 Cys229Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000492777 SCV000581119 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Invitae RCV000633388 SCV000754610 uncertain significance Li-Fraumeni syndrome 2017-08-14 criteria provided, single submitter clinical testing This sequence change replaces cysteine with arginine at codon 229 of the TP53 protein (p.Cys229Arg). The cysteine residue is moderately conserved and there is a large physicochemical difference between cysteine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in the literature individuals with breast cancer and pediatric adrenocortical carcinoma (PMID: 25925845, 25584008) ClinVar contains an entry for this variant (Variation ID: 420137). Experimental studies have shown that this missense change does not disrupt the transcriptional transactivation activity but partially affects the tumor suppressor function of TP53 protein in colony reduction assays (PMID: 12826609, 25584008). 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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