Submissions for variant NM_000546.5(TP53):c.578A>G (p.His193Arg) (rs786201838)

Total submissions: 26

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000164329	SCV000214960	likely pathogenic	Hereditary cancer-predisposing syndrome	2018-09-26	criteria provided, single submitter	clinical testing	The p.H193R variant (also known as c.578A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 578. The histidine at codon 193 is replaced by arginine, an amino acid with highly similar properties. This variant has previously been reported in an individual diagnosed with a sarcoma at age 3 and breast cancer at 29 years of age (Frebourg T et al. Am. J. Hum. Genet. 1995 Mar; 56(3):608-15). This alteration has also been reported in several unrelated individuals with early onset Li-Fraumeni spectrum tumors (Fortes FP et al. Braz. J. Med. Biol. Res. 2015 Jul;48:610-5; Bouaoun L et al. IARC TP53 database [version R18, April 2016]. Hum. Mutat. 2016 Sep;37:865-76). Multiple functional studies have shown that this variant has loss of transactivation capacity, a dominant negative effect, and reduced DNA binding activity (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; Dearth LR et al. Carcinogenesis. 2007 Feb;28:289-98). 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 majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx	RCV000255425	SCV000322118	likely pathogenic	not provided	2016-06-06	criteria provided, single submitter	clinical testing	This variant is denoted TP53 c.578A>G at the cDNA level, p.His193Arg (H193R) at the protein level, and results in the change of a Histidine to an Arginine (CAT>CGT) in exon 6. While TP53 His193Arg has been reported as one of the most commonly observed somatic TP53 variants, it has also been reported as a germline variant in one individual with a history of sarcoma and breast cancer; both cancers diagnosed at young ages (Frebourg 1995, Brachmann 2004). This variant was shown to result reduced DNA binding compared to WT for three reporter genes representing cell cycle arrest, apoptosis and auto-regulation; all three considered to be major p53 dependent pathways (Malcikova 2010). Additionally, Monti et al. (2011) considers TP53 His193Arg to be a severe deficiency allele with mean residual transactivation activity being 1%. This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Histidine and Arginine share similar properties, this is considered a conservative amino acid substitution. TP53 His193Arg occurs at a position that is conserved across species and is located within a region that interacts with HIPK1, AXIN1 and is required for interaction with ZNF385A and FBXO42 (UniProt). In silico analyses predict that this mutation is probably damaging to protein structure and function. Based on the currently available information, we consider TP53 His193Arg to be a variant, expected pathogenic.
Invitae	RCV000460847	SCV000545345	likely pathogenic	Li-Fraumeni syndrome	2020-01-07	criteria provided, single submitter	clinical testing	This sequence change replaces histidine with arginine at codon 193 of the TP53 protein (p.His193Arg). The histidine residue is highly conserved and there is a small physicochemical difference between histidine and arginine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals with a personal and/or family history of Li-Fraumeni syndrome associated tumors (PMID: 7887414, 22265402, 25945745, 28724667, Invitae). ClinVar contains an entry for this variant (Variation ID: 184979). Numerous experimental studies in model organisms have shown that this missense change disrupts the transcriptional transactivation activity of the TP53 protein, and may act in a dominant-negative manner (PMID: 9627118, 12826609, 16861262, 20128691, 21343334). 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.
Institute of Biochemistry, Molecular Biology and Biotechnology,University of Colombo	RCV000429618	SCV001450485	pathogenic	Squamous cell carcinoma of the head and neck		criteria provided, single submitter	case-control
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000255425	SCV001469323	likely pathogenic	not provided	2020-09-01	criteria provided, single submitter	clinical testing	Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Other pathogenic or likely pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Database of Curated Mutations (DoCM)	RCV000418086	SCV000508466	likely pathogenic	Breast neoplasm	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000428340	SCV000508467	likely pathogenic	Transitional cell carcinoma of the bladder	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439433	SCV000508468	likely pathogenic	Neoplasm of brain	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000418288	SCV000508469	likely pathogenic	Adenocarcinoma of stomach	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000429618	SCV000508470	likely pathogenic	Squamous cell carcinoma of the head and neck	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000439827	SCV000508471	likely pathogenic	Papillary renal cell carcinoma, sporadic	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423052	SCV000508472	likely pathogenic	Carcinoma of esophagus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000433342	SCV000508473	likely pathogenic	Small cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000440903	SCV000508474	likely pathogenic	Acute myeloid leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000423280	SCV000508475	likely pathogenic	Lung adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434391	SCV000508476	likely pathogenic	Brainstem glioma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445148	SCV000508477	likely pathogenic	Malignant neoplasm of body of uterus	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000427767	SCV000508478	likely pathogenic	Adenocarcinoma of prostate	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000434549	SCV000508479	likely pathogenic	Ovarian Serous Cystadenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000445029	SCV000508480	likely pathogenic	Squamous cell lung carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000424475	SCV000508481	likely pathogenic	Uterine Carcinosarcoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435651	SCV000508482	likely pathogenic	Hepatocellular carcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000417979	SCV000508483	likely pathogenic	Chronic lymphocytic leukemia	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000425611	SCV000508484	likely pathogenic	Pancreatic adenocarcinoma	2016-05-31	no assertion criteria provided	literature only
Database of Curated Mutations (DoCM)	RCV000435870	SCV000508485	likely pathogenic	Neoplasm of the large intestine	2016-05-31	no assertion criteria provided	literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne	RCV000785346	SCV000923914	likely pathogenic	Neoplasm of ovary	2018-12-01	no assertion criteria provided	research