Submissions for variant NM_000546.5(TP53):c.394A>G (p.Lys132Glu) (rs747342068)

Total submissions: 18

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000562533	SCV000664399	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-03-25	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Deficient protein function in appropriate functional assay(s)
Database of Curated Mutations (DoCM)	RCV000433855	SCV000508748	likely pathogenic	Uterine cervical neoplasms	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442199	SCV000508749	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426379	SCV000508750	likely pathogenic	Neoplasm of the breast	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436180	SCV000508751	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444903	SCV000508752	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425237	SCV000508753	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435981	SCV000508754	likely pathogenic	Adrenocortical carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417874	SCV000508755	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428580	SCV000508756	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434893	SCV000508757	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417803	SCV000508758	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431096	SCV000508759	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441816	SCV000508760	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423644	SCV000508761	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430828	SCV000508762	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440656	SCV000508763	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Invitae	RCV000468362	SCV000545306	uncertain significance	Li-Fraumeni syndrome	2016-12-20	criteria provided, single submitter	clinical testing	This sequence change replaces lysine with glutamic acid at codon 132 of the TP53 protein (p.Lys132Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs747342068, ExAC 0.002%). This variant has been reported in a single family affected with Li-Fraumeni syndrome. Currently there is insufficient evidence to conclude whether this variant segregates with disease or not (PMID: 9157982). Experimental studies have reported that cells carrying this missense change have reduced TP53 expression levels and transactivation activities, which results in the loss of normal TP53 functions in cell cycle and apoptosis control (PMID: 9157982, 21343334). A separate study testing TP53 transactivation activity of 8 different promoters also classifies this missense change as non-functional (PMID: 12826609). In summary, this is a rare missense change that is reported in an affected family and seen in the general population. This change has been shown to disrupt protein function in vitro and in patient cells. However, the clinical evidence available for this variant is insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.