ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.711G>T (p.Met237Ile)

dbSNP: rs587782664
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 RCV002370058 SCV002668328 likely pathogenic Hereditary cancer-predisposing syndrome 2020-01-14 criteria provided, single submitter clinical testing The p.M237I variant (also known as c.711G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 711. The methionine at codon 237 is replaced by isoleucine, an amino acid with highly similar 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). Additional studies conducted in human cell lines indicate this alteration has a dominant negative effect and 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). 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 majority of available evidence to date, this variant is likely to be pathogenic.
Baylor Genetics RCV003472321 SCV004204274 likely pathogenic Adrenocortical carcinoma, hereditary 2022-08-30 criteria provided, single submitter clinical testing
Invitae RCV003509608 SCV004365008 pathogenic Li-Fraumeni syndrome 2023-12-11 criteria provided, single submitter clinical testing This sequence change replaces methionine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 237 of the TP53 protein (p.Met237Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (PMID: 11370630; Invitae). ClinVar contains an entry for this variant (Variation ID: 634770). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 11399766, 12826609, 20407015). This variant disrupts the p.Met237 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 22109999, 29979965, 30224644; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic.
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne RCV000785508 SCV000924080 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
Laboratory of Urology, Hospital Clinic de Barcelona RCV003332249 SCV004040514 pathogenic Malignant tumor of urinary bladder no assertion criteria provided research

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.