ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.796G>C (p.Gly266Arg)

dbSNP: rs1057519990
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
Labcorp Genetics (formerly Invitae), Labcorp RCV000803659 SCV000943541 pathogenic Li-Fraumeni syndrome 2022-04-29 criteria provided, single submitter clinical testing This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 266 of the TP53 protein (p.Gly266Arg). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Li-Fraumeni syndrome (PMID: 27523101; external communication). ClinVar contains an entry for this variant (Variation ID: 376605). Advanced modeling of experimental studies (such as gene expression, population dynamics, functional pathways, and cell-cycle effects in cell culture) performed at Invitae indicates that this missense variant is expected to disrupt TP53 protein function. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16827139, 20407015, 29979965, 30224644). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV001027017 SCV001189505 pathogenic Hereditary cancer-predisposing syndrome 2019-07-02 criteria provided, single submitter clinical testing The p.G266R pathogenic mutation (also known as c.796G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 796. The glycine at codon 266 is replaced by arginine, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation 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 is deficient 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). Another alteration leading to the same amino acid change (c.796G>A) was reported in an individual with adrenocortical carcinoma and gliosarcoma and a family history of leiomyosarcoma, acute myeloid leukemia, breast cancer and melanoma (Guidi M et al. Future Oncol. 2017 Jan;13(1):9-12). In addition, another alteration at this amino acid position [p.G266E (c.797G>A)] was observed in an individual with medulloblastoma (Kool M et al. Cancer Cell. 2014 Mar; 25(3):393-405), and in patients meeting Chompret criteria (Ambry internal data). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Genome-Nilou Lab RCV001027017 SCV002582459 pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002289526 SCV002583119 pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing

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.