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. |
Gene |
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, |
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 |
RCV000418086 | SCV000508466 | likely pathogenic | Breast neoplasm | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428340 | SCV000508467 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439433 | SCV000508468 | likely pathogenic | Neoplasm of brain | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418288 | SCV000508469 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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 |
RCV000439827 | SCV000508471 | likely pathogenic | Papillary renal cell carcinoma, sporadic | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423052 | SCV000508472 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000433342 | SCV000508473 | likely pathogenic | Small cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000440903 | SCV000508474 | likely pathogenic | Acute myeloid leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000423280 | SCV000508475 | likely pathogenic | Lung adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434391 | SCV000508476 | likely pathogenic | Brainstem glioma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445148 | SCV000508477 | likely pathogenic | Malignant neoplasm of body of uterus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427767 | SCV000508478 | likely pathogenic | Adenocarcinoma of prostate | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434549 | SCV000508479 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000445029 | SCV000508480 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000424475 | SCV000508481 | likely pathogenic | Uterine Carcinosarcoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435651 | SCV000508482 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417979 | SCV000508483 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000425611 | SCV000508484 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
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, |
RCV000785346 | SCV000923914 | likely pathogenic | Neoplasm of ovary | 2018-12-01 | no assertion criteria provided | research |