Submissions for variant NM_000546.5(TP53):c.817C>A (p.Arg273Ser) (rs121913343)

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000561782	SCV000664439	pathogenic	Hereditary cancer-predisposing syndrome	2017-04-05	criteria provided, single submitter	clinical testing	Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,Structural Evidence,Other data supporting pathogenic classification
Database of Curated Mutations (DoCM)	RCV000436543	SCV000509458	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000444595	SCV000509459	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425669	SCV000509460	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435480	SCV000509461	likely pathogenic	Adenocarcinoma of prostate	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418085	SCV000509462	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427884	SCV000509463	likely pathogenic	Malignant melanoma of skin	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435074	SCV000509464	likely pathogenic	Adrenocortical carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420482	SCV000509465	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431180	SCV000509466	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440997	SCV000509467	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000420280	SCV000509468	likely pathogenic	Glioblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000430119	SCV000509469	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440794	SCV000509470	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422795	SCV000509471	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433489	SCV000509472	likely pathogenic	Multiple myeloma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439774	SCV000509473	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000422550	SCV000509474	likely pathogenic	Chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000432372	SCV000509475	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445287	SCV000509476	likely pathogenic	Neoplasm of the breast	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424918	SCV000509477	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000431455	SCV000509478	likely pathogenic	Small cell lung cancer	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445314	SCV000509479	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427515	SCV000509480	likely pathogenic	Medulloblastoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000438218	SCV000509481	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Invitae	RCV000698744	SCV000827427	likely pathogenic	Li-Fraumeni syndrome	2018-05-17	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with serine at codon 273 of the TP53 protein (p.Arg273Ser). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and serine. This variant is present in population databases (rs121913343, ExAC 0.006%). This variant has been observed in an individual affected with osteosarcoma and in two families with Li-Fraumeni syndrome (PMID: 8164043, 18685109, 25584008). ClinVar contains an entry for this variant (Variation ID: 376656). Experimental studies have shown that this missense change significantly impairs the transcriptional transactivation activity of the TP53 protein and was shown to interfere with wild-type TP53 protein function in a dominant-negative manner (PMID: 12826609, 12917626, 15017592, 21343334). The p.Arg273 amino acid residue in TP53 has been determined to be clinically significant (PMID: 2826609, 8479749, 21535297, 21552135, 17606709, 17540308, 9242456, 21484931, 1565144). This suggests that variants that disrupt this residue are likely to be causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.