Total submissions: 29
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000561782 | SCV000664439 | pathogenic | Hereditary cancer-predisposing syndrome | 2021-12-21 | 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 pathogenic mutation has been reported as a germline mutation in 1 of 235 unselected pediatric patients with osteosarcoma, as well as in a family meeting classic LFS criteria and a patient with early-onset breast cancer meeting Chompret criteria (McIntyre JF et al. J. Clin. Oncol., 1994 May;12:925-30; Tabori U et al. Cancer Res, 2007 Feb;67:1415-8; Petry V et al. Fam Cancer, 2020 01;19:47-53). This alteration occurs at a well-characterized mutation "hotspot" located within the functionally critical DNA binding domain, and has repeatedly 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). 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 alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). 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). In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the available evidence, p.R273S is classified as a pathogenic mutation. |
Invitae | RCV000698744 | SCV000827427 | pathogenic | Li-Fraumeni syndrome | 2023-12-15 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with serine, which is neutral and polar, at codon 273 of the TP53 protein (p.Arg273Ser). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with Li-Fraumeni syndrome (LFS) or Li-Fraumeni-associated cancers (PMID: 8164043, 18685109, 25584008, 31748977). ClinVar contains an entry for this variant (Variation ID: 376656). 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 with a positive predictive value of 97.5%. Experimental studies have shown that this missense change affects TP53 function (PMID: 12826609, 12917626, 15017592, 21343334, 29979965, 30224644). This variant disrupts the p.Arg273 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 1565144, 8479749, 9242456, 9407971, 10864200, 12826609, 17540308, 17606709, 20693561, 21343334, 21484931, 21535297, 21552135, 26014290, 29979965, 30224644). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
Genome- |
RCV000561782 | SCV002582454 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV002289535 | SCV002583116 | pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV002289535 | SCV004931836 | pathogenic | Li-Fraumeni syndrome 1 | 2024-02-20 | criteria provided, single submitter | clinical testing | This variant is considered pathogenic. This variant has been reported in multiple individuals with clinical features of gene-specific disease [PMID: 8164043, 17308077]. Functional studies indicate this variant impacts protein function [25584008, 27813088]. This variant is expected to disrupt protein structure [Myriad internal data]. |
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 | Prostate adenocarcinoma | 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 | Adrenal cortex 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 | Gastric adenocarcinoma | 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 | B-cell 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 |