Total submissions: 30
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 | 2023-06-16 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 231060). This variant has not been reported in the literature in individuals affected with TP53-related conditions. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces arginine, which is basic and polar, with proline, which is neutral and non-polar, at codon 273 of the TP53 protein (p.Arg273Pro). For these reasons, this variant has been classified as Pathogenic. 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, 12826609, 17540308, 17606709, 21484931, 21535297, 21552135). 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, 20516128, 22484423). 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. |
Genome- |
RCV000222860 | SCV002582452 | pathogenic | Hereditary cancer-predisposing syndrome | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Genome- |
RCV002288863 | SCV002583114 | pathogenic | Li-Fraumeni syndrome 1 | 2022-06-18 | criteria provided, single submitter | clinical testing | |
Myriad Genetics, |
RCV002288863 | SCV004932602 | likely pathogenic | Li-Fraumeni syndrome 1 | 2024-02-20 | criteria provided, single submitter | clinical testing | This variant is considered likely pathogenic. Functional studies indicate this variant impacts protein function [PMID: 7651740, 8649776, 29979965]. This variant is expected to disrupt protein structure [Myriad internal data]. |
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 | B-cell 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 | Gastric adenocarcinoma | 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 | Prostate adenocarcinoma | 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 | Adrenal cortex carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
German Consortium for Hereditary Breast and Ovarian Cancer, |
RCV000785460 | SCV000924032 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |