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

dbSNP: rs587782664

Total submissions: 5

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
Labcorp Genetics (formerly Invitae), Labcorp	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	Ovarian neoplasm	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