ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.784G>A (p.Gly262Ser) (rs200579969)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129643 SCV000184438 uncertain significance Hereditary cancer-predisposing syndrome 2017-04-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129643 SCV000686773 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-22 criteria provided, single submitter clinical testing
GeneDx RCV000590725 SCV000567260 uncertain significance not provided 2018-07-06 criteria provided, single submitter clinical testing This variant is denoted TP53 c.784G>A at the cDNA level, p.Gly262Ser (G262S) at the protein level, and results in the change of a Glycine to a Serine (GGT>AGT). This variant was observed in a woman with triple-positive breast cancer as well as her unaffected sister (Li 2016). TP53 Gly262Ser is reported in the IARC TP53 database as having non-functional transactivation based on functional assays by Kato et al. (2003). However, Leung et al. (2001) demonstrated lack of COX-2 overexpression in a gastric tumor harboring this variant, a result expected with wild-type p53. TP53 Gly262Ser 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 a deleterious effect. Based on currently available evidence, it is unclear whether TP53 Gly262Ser is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000590725 SCV000697449 uncertain significance not provided 2016-06-20 criteria provided, single submitter clinical testing Variant summary: The TP53 c.784G>A (p.Gly262Ser) variant involves the alteration of a conserved nucleotide located in the DNA binding domain, which is the target of 90% of p53 mutations found in human cancers (UMD database). 5/5 in silico tools predict a damaging outcome for this variant. This variant has been reported one family with multiple breast cancer patients, however, no detailed co-segregation analysis was performed. This variant has also been reported in numerous types of tumor samples with or without confirmed somatic status. This variant is absent in 89212 control chromosomes from ExAC. A reputable database (IARC) has reported this variant to have median transcription activity <=20% and classified it as non-functional. Other nearby missense variants have also been reported, namely p.Asn263Asp, p.Gly266Val and p.Arg267Trp; they all have been reported by a lab in ClinVar, the former two classified as uncertain significance and the last as likely pathogenic. One clinical diagnostic laboratory classified this variant as VUS. Taken together, this variant is currently classified as VUS-possibly pathogenic.
Invitae RCV000463102 SCV000545274 uncertain significance Li-Fraumeni syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces glycine with serine at codon 262 of the TP53 protein (p.Gly262Ser). The glycine residue is highly conserved and there is a small physicochemical difference between glycine and serine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in a family affected with breast cancer (PMID: 26534844). ClinVar contains an entry for this variant (Variation ID: 141228). An experimental study in yeast has shown that this variant impairs the transcriptional transactivation activity of the TP53 protein (PMID: 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.

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.