Total submissions: 21
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000131246 | SCV000186204 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-10-19 | criteria provided, single submitter | clinical testing | The p.R249K pathogenic mutation (also known as c.746G>A), located in coding exon 6 of the TP53 gene, results from a G to A substitution at nucleotide position 746. The arginine at codon 249 is replaced by lysine, an amino acid with highly similar properties. This alteration was reported in one child with adrenal cortical carcinoma (Ambry internal data). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity in yeast based functional assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has a dominant negative effect (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). 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 supporting evidence, this alteration is interpreted as a disease-causing mutation. |
Eurofins Ntd Llc |
RCV000724753 | SCV000232077 | uncertain significance | not provided | 2015-04-22 | criteria provided, single submitter | clinical testing | |
Gene |
RCV000724753 | SCV000567602 | uncertain significance | not provided | 2015-08-06 | criteria provided, single submitter | clinical testing | This variant is denoted TP53 c.746G>A at the cDNA level, p.Arg249Lys (R249K) at the protein level, and results in the change of an Arginine to a Lysine (AGG>AAG). This variant has not, to our knowledge, been published in the literature as a germline variant; however, TP53 Arg249Lys has been reported as a somatic variant in multiple different tumor types (Cosmic, IARC TP53 Database). TP53 Arg249Lys has also been reported as having non-functional transactivation activity in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003) and demonstrated reduced transcriptional activity in a yeast functional assay (Van der Vorst 2012). TP53 Arg249Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Arginine and Lysine share similar properties, this is considered a conservative amino acid substitution. TP53 Arg249Lys occurs at a position that is conserved across species and is located in the region of interaction with CCAR2, HIPK1, and ZNF385A (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether TP53 Arg249Lys is pathogenic or benign. We consider it to be a variant of uncertain significance. |
Invitae | RCV001857457 | SCV002259639 | uncertain significance | Li-Fraumeni syndrome | 2023-03-04 | criteria provided, single submitter | clinical testing | In summary, 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. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 29979965). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. ClinVar contains an entry for this variant (Variation ID: 142241). This missense change has been observed in individual(s) with breast or ovarian cancer (PMID: 26786923, 30546832). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 249 of the TP53 protein (p.Arg249Lys). |
Genome- |
RCV000131246 | SCV002582008 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV002288647 | SCV002582035 | uncertain significance | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Database of Curated Mutations |
RCV000420497 | SCV000509419 | likely pathogenic | Medulloblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427275 | SCV000509420 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437502 | SCV000509421 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419850 | SCV000509422 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430131 | SCV000509423 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440358 | SCV000509424 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419499 | SCV000509425 | likely pathogenic | Uterine carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429319 | SCV000509426 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439985 | SCV000509427 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421887 | SCV000509428 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429077 | SCV000509429 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438874 | SCV000509430 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421647 | SCV000509431 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431473 | SCV000509432 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445113 | SCV000509433 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only |