ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.466C>T (p.Arg156Cys) (rs563378859)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213051 SCV000149630 uncertain significance not provided 2018-04-07 criteria provided, single submitter clinical testing This variant is denoted TP53 c.466C>T at the cDNA level, p.Arg156Cys (R156C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been observed in at least three individuals with breast cancer (Sun 2017). Functional assays of TP53 Arg156Cys demonstrated transcription activity similar to wild type (Kakudo 2005), and 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 Arg156Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the DNA-binding domain (Bode 2004). 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 Arg156Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115721 SCV000185652 uncertain significance Hereditary cancer-predisposing syndrome 2020-08-07 criteria provided, single submitter clinical testing The p.R156C variant (also known as c.466C>T) is located in coding exon 4 of the TP53 gene. This alteration results from a C to T substitution at nucleotide position 466. The arginine at codon 156 is replaced by cysteine, an amino acid with highly dissimilar properties. This alteration has been observed in a series of unselected breast cancer probands from China (Sun J et al. Clin. Cancer Res. 2017 Oct;23(20):6113-6119). This variant is in the DNA binding domain of the TP53 protein and is reported to have partially functional transactivation capacity in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is not well conserved in available vertebrate species, with cysteine being the reference allele in multiple species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this variant remains unclear.
Invitae RCV000232885 SCV000285198 uncertain significance Li-Fraumeni syndrome 2020-10-02 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 156 of the TP53 protein (p.Arg156Cys). The arginine residue is moderately conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast cancer (PMID: 28724667). ClinVar contains an entry for this variant (Variation ID: 127810). An experimental study in yeast has shown that this variant partially impairs the transcriptional transactivation activity of the TP53 protein (PMID: 12826609), whereas others demonstrate this variant to not have an impact on protein function (PMID: 29979965, 30224644). Furthermore, in vitro studies in human osteosarcoma Saos-2 cells demonstrate that this variant results in an increased ability to induce apoptosis, but has no effect on TP53 dependent transcriptional activity (PMID: 15781620). 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.
Counsyl RCV000409094 SCV000488318 uncertain significance Li-Fraumeni syndrome 1 2016-02-25 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000764146 SCV000895131 uncertain significance Adrenocortical carcinoma, hereditary; Familial cancer of breast; Glioma susceptibility 1; Osteosarcoma; Li-Fraumeni syndrome 1; Nasopharyngeal carcinoma; Carcinoma of pancreas; Choroid plexus papilloma; Carcinoma of colon; Basal cell carcinoma, susceptibility to, 7; Hepatocellular carcinoma 2018-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000115721 SCV000911117 likely benign Hereditary cancer-predisposing syndrome 2017-01-27 criteria provided, single submitter clinical testing

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