ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.868C>T (p.Arg290Cys) (rs770374782)

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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 RCV000492120 SCV000581102 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000492120 SCV000904079 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-28 criteria provided, single submitter clinical testing
GeneDx RCV000236248 SCV000292985 uncertain significance not provided 2017-11-16 criteria provided, single submitter clinical testing This variant is denoted TP53 c.868C>T at the cDNA level, p.Arg290Cys (R290C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has not, to our knowledge, been published in the literature as either a germline pathogenic variant or a benign polymorphism. However, this variant has been reported as a somatic variant in multiple neoplasms, including leukemias, an oligodendroma, squamous cell carcinomas, endometrial cancer and a soft tissue sarcoma (Dicker 2009, Ito 2011, Mellai 2011, Wild 2012, Lechner 2013, Jeromin 2014, Li 2015). TP53 Arg290Cys was associated with a median transactivational activity categorized as functional" in a yeast-based assay (Petitjean 2007). TP53 Arg290Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Arginine and Cysteine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Arg290Cys is located in the DNA-binding domain (Bode 2004). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available information, it is unclear whether TP53 Arg290Cys is pathogenic or benign. We consider it to be a variant of uncertain significance."
Invitae RCV000198910 SCV000254642 uncertain significance Li-Fraumeni syndrome 2018-12-22 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 290 of the TP53 protein (p.Arg290Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs770374782, ExAC 0.01%). This variant has been reported in the literature in individuals affected with breast cancer and osteosarcoma (PMID: 25503501, 25512523). ClinVar contains an entry for this variant (Variation ID: 216472). Experimental studies have shown that this variant does not have an impact on protein function, with transactivation activities equivalent to wild-type TP53 (PMID: 17311302, 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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