Submissions for variant NM_000546.5(TP53):c.818G>T (p.Arg273Leu) (rs28934576)

Total submissions: 28

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000568814	SCV000665156	pathogenic	Hereditary cancer-predisposing syndrome	2017-08-18	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,Confirmed de novo alteration in the setting of a new disease (appropriate phenotype) in the family,Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,Other strong data supporting pathogenic classification,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Database of Curated Mutations (DoCM)	RCV000423981	SCV000509434	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434695	SCV000509435	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444989	SCV000509436	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427314	SCV000509437	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000437048	SCV000509438	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444109	SCV000509439	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000426132	SCV000509440	likely pathogenic	Adrenocortical carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000436818	SCV000509441	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418738	SCV000509442	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429444	SCV000509443	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435767	SCV000509444	likely pathogenic	Small cell lung cancer	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418536	SCV000509445	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428692	SCV000509446	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438507	SCV000509447	likely pathogenic	Neoplasm of the breast	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000421259	SCV000509448	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431067	SCV000509449	likely pathogenic	Adenocarcinoma of prostate	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000441792	SCV000509450	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423633	SCV000509451	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434296	SCV000509452	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000442241	SCV000509453	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423490	SCV000509454	likely pathogenic	Chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433315	SCV000509455	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444782	SCV000509456	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425890	SCV000509457	likely pathogenic	Medulloblastoma	2016-05-31	no assertion criteria provided	literature only
Genome Sciences Centre,British Columbia Cancer Agency	RCV000515526	SCV000611151	likely pathogenic	Metastatic pancreatic neuroendocrine tumours	2017-11-01	no assertion criteria provided	research
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne	RCV000785524	SCV000924096	likely pathogenic	Ovarian Neoplasms	2018-12-01	no assertion criteria provided	research
Invitae	RCV000822080	SCV000962866	pathogenic	Li-Fraumeni syndrome	2018-11-09	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with leucine at codon 273 of the TP53 protein (p.Arg273Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is present in population databases (rs28934576, ExAC 0.002%). This variant has been observed in individuals affected with Li-Fraumeni-associated cancers (PMID: 10864200, 26014290). In one of this individuals the variant was observed to be de novo (PMID: 10864200). ClinVar contains an entry for this variant (Variation ID: 376655). Experimental studies have shown that this missense change impairs the transcriptional transactivation activity of the TP53 protein (PMID: 9407971, 12826609, 21343334). This variant disrupts the p.273 amino acid residue in TP53. Other variants that disrupt this residue have been observed in affected individuals (PMID: 9242456, 21484931, 17540308, 1565144, 20693561, 21552135), suggesting that it is a clinically significant residue. As a result, variants that disrupt this residue are likely to be causative of disease. For these reasons, this variant has been classified as Pathogenic.