Submissions for variant NM_000546.5(TP53):c.581T>G (p.Leu194Arg) (rs1057519998)

Total submissions: 14

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561306	SCV000676299	uncertain significance	Hereditary cancer-predisposing syndrome	2016-02-09	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Insufficient or conflicting evidence,Co-occurence with mutation in same gene (phase unknown),Other data supporting pathogenic classification
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	Neoplasm of the breast	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	Uterine cervical neoplasms	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 Center Cologne,University Hospital Cologne	RCV000785551	SCV000924123	likely pathogenic	Ovarian Neoplasms	2018-12-01	no assertion criteria provided	research
Invitae	RCV000535418	SCV000629844	uncertain significance	Li-Fraumeni syndrome	2018-01-10	criteria provided, single submitter	clinical testing	This sequence change replaces leucine with arginine at codon 194 of the TP53 protein (p.Leu194Arg). The leucine residue is highly conserved and there is a moderate physicochemical difference between leucine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 376633). Experimental studies in yeast and human non-small cell lung carcinoma cell lines demonstrate that this missense change has defective transactivation activity, does not interact with MDM2, fails to suppress cell growth, and has reduced induction of TP53 downstream target genes following fludarabine administration (PMID: 12826609, 20407015, 12509279, 19850740). 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.