Total submissions: 27
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Ambry Genetics | RCV000222860 | SCV000274797 | pathogenic | Hereditary cancer-predisposing syndrome | 2020-09-03 | criteria provided, single submitter | clinical testing | The p.R273P pathogenic mutation (also known as c.818G>C), located in coding exon 7 of the TP53 gene, results from a G to C substitution at nucleotide position 818. The arginine at codon 273 is replaced by proline, an amino acid with dissimilar properties. This alteration occurs at a well-characterized mutation hotspot with other amino acid changes at codon 273 described in LFS families (Janavicius et al. The Breast Journall. 2011; 17(4): 409-415; Masciari, S et al. Genet Med. 2011 Jul;13(7):651-7; Brugières L et al, Cancer Res. 1993 Feb; 53(3):452-5; Stenson et al. The Human Gene Mutation Database (HGMD®): 2003 Update. Hum Mutat. 2003;21:577-581). In addition, this variant is located in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, moderate dominant negative effect, and predicted to affect several p53 isoforms in yeast based assays (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). 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). Based on internal structural analysis, this variant is anticipated to result in a significant decrease in structural stability (Canadillas J et al. Proc. Natl. Acad. Sci. U.S.A. 2006 Feb;103(7):2109-14). 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. |
Invitae | RCV000553607 | SCV000629874 | pathogenic | Li-Fraumeni syndrome | 2017-07-18 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine with proline at codon 273 of the TP53 protein (p.Arg273Pro). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and proline. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in the germline of individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 231060). This variant is located in the DNA-binding domain of the TP53 protein and eliminates an essential DNA contact (PMID: 20516128). Experimental studies have shown that this missense change disrupts the transactivation activity of the TP53 protein (PMID: 12826609, 22484423). Different missense substitutions at this codon (p.Arg273His, p.Arg273Cys) has been determined to be pathogenic (PMID: 12826609, 8479749, 21535297, 21552135, 17606709, 17540308, 9242456, 21484931, 1565144). This suggests that the arginine residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic. |
Database of Curated Mutations |
RCV000420123 | SCV000509482 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427328 | SCV000509483 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437116 | SCV000509484 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419898 | SCV000509485 | likely pathogenic | Malignant melanoma of skin | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429654 | SCV000509486 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440313 | SCV000509487 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418732 | SCV000509488 | likely pathogenic | Multiple myeloma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429434 | SCV000509489 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439246 | SCV000509490 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422030 | SCV000509491 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431835 | SCV000509492 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439039 | SCV000509493 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000421059 | SCV000509494 | likely pathogenic | Squamous cell carcinoma of the head and neck | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000431744 | SCV000509495 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000442511 | SCV000509496 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427811 | SCV000509497 | likely pathogenic | Medulloblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434099 | SCV000509498 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000444938 | SCV000509499 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426712 | SCV000509500 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000437377 | SCV000509501 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419328 | SCV000509502 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000426561 | SCV000509503 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000436356 | SCV000509504 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000419080 | SCV000509505 | likely pathogenic | Adrenocortical carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne, |
RCV000785460 | SCV000924032 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |