Submissions for variant NM_000546.6(TP53):c.746G>T (p.Arg249Met)

dbSNP: rs587782329

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000690948	SCV000818679	uncertain significance	Li-Fraumeni syndrome	2024-09-03	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with methionine, which is neutral and non-polar, at codon 249 of the TP53 protein (p.Arg249Met). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 376653). Invitae Evidence Modeling incorporating data from in vitro 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: 12826609, 15037740, 29979965, 30224644). 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.
Myriad Genetics, Inc.	RCV004022239	SCV004933224	likely pathogenic	Li-Fraumeni syndrome 1	2024-02-16	criteria provided, single submitter	clinical testing	This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 15037740, 17999388, 25294809, 8001119, 8843196, 12509279]. This variant is expected to disrupt protein structure [Myriad internal data].
Ambry Genetics	RCV004948281	SCV005522071	pathogenic	Hereditary cancer-predisposing syndrome	2024-08-21	criteria provided, single submitter	clinical testing	The p.R249M pathogenic mutation (also known as c.746G>T), located in coding exon 6 of the TP53 gene, results from a G to T substitution at nucleotide position 746. The arginine at codon 249 is replaced by methionine, an amino acid with similar properties. Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). 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). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). Two other variants at the same codon, p.R249K (c.746G>A) and p.R249T (c.746G>C), are functionally deficient across functional studies (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; 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. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this variant is interpreted as a disease-causing mutation.
Western Connecticut Health Network, Rudy L. Ruggles Biomedical Research Institute	RCV000782360	SCV000902407	pathogenic	Ovarian neoplasm	2018-10-15	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000782360	SCV000923861	likely pathogenic	Ovarian neoplasm	2018-12-01	no assertion criteria provided	research