Total submissions: 24
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000129010 | SCV000172907 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-10-28 | criteria provided, single submitter | clinical testing | The p.R282G pathogenic mutation (also known as c.844C>G), located in coding exon 7 of the TP53 gene, results from a C to G substitution at nucleotide position 844. The arginine at codon 282 is replaced by glycine, an amino acid with dissimilar properties. This mutation is in the DNA binding domain of the p53 protein and is reported to have loss of transactivation capacity and predicted to affect several p53 isoforms (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 (Kotler E et al. Mol.Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-1387). It was previously identified in a patient with primary orbital liposarcoma whose family met diagnostic criteria for Li-Fraumeni syndrome (LFS) (Poli T et al. Tumori; 91:96-100). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Additionally, two other missense mutations occurring at the same codon have been reported (p.R282Q and p.R282W). In one study, the p.R282Q mutation was reported in a 14-year-old male with a soft tissue sarcoma who was later diagnosed with an osteosarcoma and lung cancer (Chompret et al. 2000 British J Cancer 82(12):1932-1937). The p.R282W mutation was detected in a patient with contralateral breast cancer at age 32 (Heyman et al. 2010 Radiation Oncology 5:104), and in a kindred with clinical LFS, however, specific clinical information was not provided (Wu et al. 2011 Hum Genet 129:663-673). Based on the supporting evidence, the p.R282G alteration is interpreted as a disease-causing mutation. |
Invitae | RCV001380073 | SCV001578015 | pathogenic | Li-Fraumeni syndrome | 2023-04-17 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 282 of the TP53 protein (p.Arg282Gly). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Arg282 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565143, 1565144, 11370630, 12826609, 17606709, 19468865, 21305319, 21761402, 22672556, 25584008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 21343334, 23246812, 29979965, 30224644). 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: 140821). This missense change has been observed in individuals with clinical features of Li-Fraumeni Syndrome (PMID: 15850016, 26014290, 26556299, 28802053). This variant is not present in population databases (gnomAD no frequency). |
Genome- |
RCV000129010 | SCV002582449 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV002288620 | SCV002583111 | pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Database of Curated Mutations |
RCV000440446 | SCV000509593 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422747 | SCV000509594 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430393 | SCV000509595 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440653 | SCV000509596 | likely pathogenic | Papillary renal cell carcinoma type 1 | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422134 | SCV000509597 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432433 | SCV000509598 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442627 | SCV000509599 | likely pathogenic | Ovarian serous cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422367 | SCV000509600 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431764 | SCV000509601 | likely pathogenic | Gastric adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442540 | SCV000509602 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425179 | SCV000509603 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435503 | SCV000509604 | likely pathogenic | Squamous cell carcinoma of the skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445294 | SCV000509605 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427647 | SCV000509606 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437895 | SCV000509607 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419333 | SCV000509608 | likely pathogenic | Non-Hodgkin lymphoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430047 | SCV000509609 | likely pathogenic | Prostate adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437219 | SCV000509610 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419993 | SCV000509611 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785299 | SCV000923867 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |