Submissions for variant NM_000546.6(TP53):c.581T>G (p.Leu194Arg)

dbSNP: rs1057519998

Total submissions: 15

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000535418	SCV000629844	uncertain significance	Li-Fraumeni syndrome	2023-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 194 of the TP53 protein (p.Leu194Arg). This variant is present in population databases (no rsID available, gnomAD 0.01%). 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: 376633). 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12509279, 12826609, 20407015, 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.
Ambry Genetics	RCV000561306	SCV000676299	pathogenic	Hereditary cancer-predisposing syndrome	2021-08-12	criteria provided, single submitter	clinical testing	The p.L194R variant (also known as c.581T>G), located in coding exon 5 of the TP53 gene, results from a T to G substitution at nucleotide position 581. The leucine at codon 194 is replaced by arginine, 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 in yeast based assays (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 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 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.
Institute of Biochemistry, Molecular Biology and Biotechnology, University of Colombo	RCV001270270	SCV001450486	pathogenic	Colorectal cancer		criteria provided, single submitter	case-control
Database of Curated Mutations (DoCM)	RCV000424933	SCV000508836	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437791	SCV000508837	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420755	SCV000508838	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431014	SCV000508839	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436915	SCV000508840	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419180	SCV000508841	likely pathogenic	Neoplasm of uterine cervix	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430366	SCV000508842	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440633	SCV000508843	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422070	SCV000508844	likely pathogenic	Ovarian serous cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428827	SCV000508845	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439886	SCV000508846	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne	RCV000785551	SCV000924123	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research