Total submissions: 26
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000561782 | SCV000664439 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-04-05 | criteria provided, single submitter | clinical testing | The p.R273S pathogenic mutation (also known as c.817C>A), located in coding exon 7 of the TP53 gene, results from a C to A substitution at nucleotide position 817. The arginine at codon 273 is replaced by serine, an amino acid with dissimilar properties. This amino acid position is highly conserved in available vertebrate species. This alteration occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain, and has repededly shown loss of transactivation capacity in yeast-based functional studies (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Mitsumoto Y et al. Hum. Pathol., 2004 Mar;35:350-6; Monti P et al. Oncogene, 2003 Aug;22:5252-60; Monti P et al. Mol. Cancer Res., 2011 Mar;9:271-9). This pathogenic mutation has been reported as a germline mutation in 1 of 235 unselected pediatric patients with osteosarcoma (McIntyre JF et al. J. Clin. Oncol., 1994 May;12:925-30). This alteration has been described as “oncomorphic”, or gain-of-function, secondary to functional analysis indicating a loss of interaction with the microprocessing Drosha complex (Brachova P et al. J Cancer Ther, 2014 Jun;5:506-516). Further, crystal structure analysis indicates this position is involved in DNA contact and binding (Martin A et al., Hum. Mutat. 2002 Feb; 19(2):149-64). Based on the available evidence, p.R273S is classified as a pathogenic mutation. |
Invitae | RCV000698744 | SCV000827427 | likely pathogenic | Li-Fraumeni syndrome | 2019-12-23 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with serine at codon 273 of the TP53 protein (p.Arg273Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs121913343, ExAC 0.006%). This variant has been observed in an individual affected with osteosarcoma and in two families with Li-Fraumeni syndrome (PMID: 8164043, 18685109, 25584008). ClinVar contains an entry for this variant (Variation ID: 376656). Experimental studies have shown that this missense change significantly impairs the transcriptional transactivation activity of the TP53 protein and was shown to interfere with wild-type TP53 protein function in a dominant-negative manner (PMID: 12826609, 12917626, 15017592, 21343334). The p.Arg273 amino acid residue in TP53 has been determined to be clinically significant (PMID: 2826609, 8479749, 21535297, 21552135, 17606709, 17540308, 9242456, 21484931, 1565144). This suggests that variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. |
Database of Curated Mutations |
RCV000436543 | SCV000509458 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444595 | SCV000509459 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425669 | SCV000509460 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435480 | SCV000509461 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418085 | SCV000509462 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427884 | SCV000509463 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435074 | SCV000509464 | likely pathogenic | Adrenocortical carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420482 | SCV000509465 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431180 | SCV000509466 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440997 | SCV000509467 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000420280 | SCV000509468 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000430119 | SCV000509469 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440794 | SCV000509470 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422795 | SCV000509471 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433489 | SCV000509472 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439774 | SCV000509473 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422550 | SCV000509474 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000432372 | SCV000509475 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445287 | SCV000509476 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424918 | SCV000509477 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431455 | SCV000509478 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445314 | SCV000509479 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427515 | SCV000509480 | likely pathogenic | Medulloblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000438218 | SCV000509481 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only |