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

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 (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