ClinVar Miner

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

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Total submissions: 19
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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

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