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

Total submissions: 19

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
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.
Ambry Genetics	RCV000562533	SCV000664399	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-10-31	criteria provided, single submitter	clinical testing	The p.K132E variant (also known as c.394A>G), located in coding exon 4 of the TP53 gene, results from an A to G substitution at nucleotide position 394. The lysine at codon 132 is replaced by glutamic acid, an amino acid with similar properties. This alteration has been reported in an individual diagnosed with rhabdomyosarcoma at age 2 and osteosarcoma at age 11 and have two relatives in two generations diagnosed with breast cancer (IARC TP53 database). In a study of TP53 genotype-phenotype associations, this variant was classified as a severe deficiency allele based on in vitro luciferase assays (Monti P et al, Mol Cancer Res 2011. 9:271-279). The authors observed that severe deficiency alleles are associated with more severe clinical features than alleles classified as partial deficiency. This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, dominant negative effect and predicted to affect several p53 isoforms in yeast based assays (Chappuis PO et al. Int. J. Cancer 1999 Dec; 84(6):587-93; IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9(3):271-9). This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. 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 majority of available evidence to date, this variant is likely to be pathogenic.
Institute of Human Genetics, University of Leipzig Medical Center	RCV001253548	SCV001429318	pathogenic	Li-Fraumeni syndrome 1	2020-09-01	criteria provided, single submitter	clinical testing
Database of Curated Mutations (DoCM)	RCV000433855	SCV000508748	likely pathogenic	Neoplasm of uterine cervix	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	Breast neoplasm	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