ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.738G>A (p.Met246Ile) (rs1019340046)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561491 SCV000664977 likely pathogenic Hereditary cancer-predisposing syndrome 2017-04-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Deficient protein function in appropriate functional assay(s),Other data supporting pathogenic classification,Structural Evidence
Invitae RCV000633390 SCV000754612 uncertain significance Li-Fraumeni syndrome 2017-11-27 criteria provided, single submitter clinical testing This sequence change replaces methionine with isoleucine at codon 246 of the TP53 protein (p.Met246Ile). The methionine residue is highly conserved and there is a small physicochemical difference between methionine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related disease. Experimental studies have shown that this variant impairs the transcriptional transactivation activity and promoter binding efficiency of the TP53 protein (PMID: 12826609, 10777217). Studies in a cancer cell line containing this variant have reported conflicting results regarding the effects of this variant on TP53 function (PMID: 25881545, 26181206, 8336941, 22198284) A different missense substitution at this codon (p.Arg175His) has been determined to be pathogenic (PMID: 8825920, 8164043, 16401470, 23792586, 23263379, 15607980, 15607981). This suggests that the methionine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. 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.