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, |
RCV001253548 | SCV001429318 | pathogenic | Li-Fraumeni syndrome 1 | 2020-09-01 | criteria provided, single submitter | clinical testing | |
Database of Curated Mutations |
RCV000433855 | SCV000508748 | likely pathogenic | Neoplasm of uterine cervix | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442199 | SCV000508749 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426379 | SCV000508750 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436180 | SCV000508751 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444903 | SCV000508752 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425237 | SCV000508753 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435981 | SCV000508754 | likely pathogenic | Adrenocortical carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000428580 | SCV000508756 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434893 | SCV000508757 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417803 | SCV000508758 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431096 | SCV000508759 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000441816 | SCV000508760 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423644 | SCV000508761 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430828 | SCV000508762 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440656 | SCV000508763 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only |