Submissions for variant NM_000546.6(TP53):c.745A>T (p.Arg249Trp)

dbSNP: rs587782082

Total submissions: 21

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000130578	SCV000185450	pathogenic	Hereditary cancer-predisposing syndrome	2023-12-01	criteria provided, single submitter	clinical testing	The p.R249W pathogenic mutation (also known as c.745A>T), located in coding exon 6 of the TP53 gene, results from an A to T substitution at nucleotide position 745. The arginine at codon 249 is replaced by tryptophan, an amino acid with dissimilar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based functional assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). 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 alteration, as well as other alterations at codon 249, have been observed numerous times somatically in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183); however, germline observations have not been reported. 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 alteration is interpreted as a disease-causing mutation.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden	RCV003237740	SCV002011363	likely pathogenic	not provided	2021-11-03	criteria provided, single submitter	clinical testing
Invitae	RCV002514731	SCV003211441	uncertain significance	Li-Fraumeni syndrome	2023-05-01	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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 16861262, 23612969, 29979965, 30224644). 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. ClinVar contains an entry for this variant (Variation ID: 141881). This variant has not been reported in the literature in individuals affected with TP53-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with tryptophan, which is neutral and slightly polar, at codon 249 of the TP53 protein (p.Arg249Trp).
Baylor Genetics	RCV003460931	SCV004206254	pathogenic	Adrenocortical carcinoma, hereditary	2023-07-16	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV004019741	SCV004933127	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: 29979965]. This variant is expected to disrupt protein structure [Myriad internal data].
Database of Curated Mutations (DoCM)	RCV000432429	SCV000504692	likely pathogenic	Acute myeloid leukemia	2014-10-02	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434278	SCV000509389	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440994	SCV000509390	likely pathogenic	Medulloblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423307	SCV000509391	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433563	SCV000509392	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444809	SCV000509393	likely pathogenic	Gastric adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426167	SCV000509394	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432948	SCV000509395	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000443796	SCV000509396	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425504	SCV000509397	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435888	SCV000509398	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418238	SCV000509399	likely pathogenic	Uterine carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424980	SCV000509400	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435249	SCV000509401	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417537	SCV000509402	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431276	SCV000509403	likely pathogenic	Prostate adenocarcinoma	2016-05-31	no assertion criteria provided	literature only