ClinVar Miner

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

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000198910 SCV000254642 uncertain significance Li-Fraumeni syndrome 2020-10-29 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). This variant has been reported not to substantially affect TP53 protein function (PMID: 17311302, 12826609, 29979965, 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.
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."
Ambry Genetics RCV000492120 SCV000581102 likely benign Hereditary cancer-predisposing syndrome 2019-11-04 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Color Health, Inc RCV000492120 SCV000904079 uncertain significance Hereditary cancer-predisposing syndrome 2020-12-02 criteria provided, single submitter clinical testing This missense variant replaces arginine with cysteine at codon 290 of the TP53 protein. Computational prediction suggests that this variant may impact protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown the mutant protein to function normally in yeast transactivation assay (PMID: 12826609) and human cell growth assays (PMID: 29979965, 30224644). This variant has been reported in individuals affected with early-onset breast cancer (PMID: 25503501) and osteosarcoma (PMID: 25512523). This variant has been identified in 4/282870 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 information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.