Submissions for variant NM_000546.5(TP53):c.374C>G (p.Thr125Arg) (rs786201057)

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000492090	SCV000581128	likely pathogenic	Hereditary cancer-predisposing syndrome	2014-11-20	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Rarity in general population databases (dbsnp, esp, 1000 genomes),Other data supporting pathogenic classification,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation
Database of Curated Mutations (DoCM)	RCV000428977	SCV000509821	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440628	SCV000509822	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423368	SCV000509823	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429727	SCV000509824	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440402	SCV000509825	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424026	SCV000509826	likely pathogenic	Squamous cell carcinoma of the skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434737	SCV000509827	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442755	SCV000509828	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423812	SCV000509829	likely pathogenic	Renal cell carcinoma, papillary, 1	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432131	SCV000509830	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442833	SCV000509831	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424710	SCV000509832	likely pathogenic	Small cell lung cancer	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436286	SCV000509833	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442028	SCV000509834	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425385	SCV000509835	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436088	SCV000509836	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419630	SCV000509837	likely pathogenic	Neoplasm of the breast	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430321	SCV000509838	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436638	SCV000509839	likely pathogenic	Adrenocortical carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000419385	SCV000509840	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Invitae	RCV000524926	SCV000629809	uncertain significance	Li-Fraumeni syndrome	2018-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces threonine with arginine at codon 125 of the TP53 protein (p.Thr125Arg). The threonine residue is highly conserved and there is a moderate physicochemical difference between threonine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in several individuals affected with Li-Fraumeni syndrome cancers (PMID: 18511570, 20127978, 20522432), and an individual with hypodiploid acute lymphoblastic leukemia (PMID: 26580448). ClinVar contains an entry for this variant (Variation ID: 376667). Experimental studies have shown that this variant disrupts the function of the TP53 protein (PMID: 12826609, 16508005, 27533082, 17401428). In summary, this variant is a rare missense change that is absent from the population, reported in affected individuals, and has been shown to disrupt protein function in vitro. However, 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.