Submissions for variant NM_000546.6(TP53):c.737T>G (p.Met246Arg)

dbSNP: rs587780074

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115734	SCV000149643	likely pathogenic	not provided	2019-09-18	criteria provided, single submitter	clinical testing	Not observed in large population cohorts (Lek 2016); In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect; This variant is associated with the following publications: (PMID: 30923319, 29979965, 30224644, 31127692, 24853695, 8829653, 8633021, 16861262, 10519380)
Labcorp Genetics (formerly Invitae), Labcorp	RCV001344441	SCV001538494	uncertain significance	Li-Fraumeni syndrome	2021-04-16	criteria provided, single submitter	clinical testing	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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. Experimental studies have shown that this variant affects TP53 protein function (PMID: 12826609, 30224644). This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 127822). This variant is not present in population databases (ExAC no frequency). This sequence change replaces methionine with arginine at codon 246 of the TP53 protein (p.Met246Arg). The methionine residue is highly conserved and there is a moderate physicochemical difference between methionine and arginine.
Ambry Genetics	RCV002381420	SCV002672106	pathogenic	Hereditary cancer-predisposing syndrome	2022-03-31	criteria provided, single submitter	clinical testing	The p.M246R pathogenic mutation (also known as c.737T>G), located in coding exon 6 of the TP53 gene, results from a T to G substitution at nucleotide position 737. The methionine at codon 246 is replaced by arginine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Two other alterations at the same codon, p.M246V (c.736A>G) and p.M246L (c.736A>C), have been described in individuals clinical histories suggestive of LFS and/or have reported deleterious functional and structural studies (Bardeesy N et al Nat. Genet. 1994 May;7(1):91-7; Cho Y et al. Science. 1994 Jul; 265(5170):346-55; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Oncogene. 2002 Mar; 21(11):1641-8; Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). 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.