ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.818G>C (p.Arg273Pro) (rs28934576)

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Total submissions: 27
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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 (DoCM) RCV000420123 SCV000509482 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427328 SCV000509483 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437116 SCV000509484 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419898 SCV000509485 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429654 SCV000509486 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440313 SCV000509487 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418732 SCV000509488 likely pathogenic Multiple myeloma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429434 SCV000509489 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439246 SCV000509490 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422030 SCV000509491 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431835 SCV000509492 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439039 SCV000509493 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) 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 (DoCM) RCV000431744 SCV000509495 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442511 SCV000509496 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427811 SCV000509497 likely pathogenic Medulloblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434099 SCV000509498 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444938 SCV000509499 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426712 SCV000509500 likely pathogenic Adenocarcinoma of prostate 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000437377 SCV000509501 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419328 SCV000509502 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426561 SCV000509503 likely pathogenic Malignant neoplasm of body of uterus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436356 SCV000509504 likely pathogenic Brainstem glioma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) 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,University Hospital Cologne RCV000785460 SCV000924032 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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