ClinVar Miner

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

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Total submissions: 26
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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 2020-10-02 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). Experimental studies have shown that this variant affects TP53 protein function (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

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