Total submissions: 15
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Clin |
RCV000477234 | SCV001142540 | likely pathogenic | Li-Fraumeni syndrome | 2019-08-28 | reviewed by expert panel | curation | This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). Transactivation assays show a low functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3; PMID: 12826609, 30224644). This variant has >10 observations as a somatic hotspot variant in tumors (PM1; cancerhotspots.org v(2)). Additionally, this variant has been reported in 2 probands meeting Chompret criteria (PS4_Supporting; PMID: 20522432, ClinVar SCV000581129.3). In summary, TP53 c.641A>G; p.His214Arg meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PS3, PM1, PS4_Supporting. |
Invitae | RCV000477234 | SCV000545273 | uncertain significance | Li-Fraumeni syndrome | 2019-11-27 | criteria provided, single submitter | clinical testing | This sequence change replaces histidine with arginine at codon 214 of the TP53 protein (p.His214Arg). 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 observed in an individual affected with Li-Fraumeni syndrome (PMID: 20522432). ClinVar contains an entry for this variant (Variation ID: 376615). Experimental studies have shown that this missense change impacts protein function (PMID: 12826609, 9546439, 7732013, 10761705, 11920959). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. |
Ambry Genetics | RCV000492372 | SCV000581129 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2019-02-19 | criteria provided, single submitter | clinical testing | The p.H214R variant (also known as c.641A>G), located in coding exon 5 of the TP53 gene, results from an A to G substitution at nucleotide position 641. The histidine at codon 214 is replaced by arginine, an amino acid with highly similar properties. This alteration is located in the DNA binding domain and has been shown to be temperature sensitive, and have a loss of transactivation capability in yeast-based functional studies (Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Yamamoto S et al. Jpn. J. Cancer Res. 2000 Feb; 91(2):181-9; Flaman JM et al. Oncogene 1998 Mar; 16(10):1369-72). This variant was detected in an individual meeting Chompret criteria with breast cancer at 35, brain cancer at 40, and adrenocortical carcinoma at 41 (Ruijs MW et al. J. Med. Genet. 2010 Jun; 47(6):421-8). This amino acid position is highly conserved through mammals on sequence alignment. 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. |
Color | RCV000492372 | SCV001358774 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2018-09-08 | criteria provided, single submitter | clinical testing | |
Database of Curated Mutations |
RCV000445232 | SCV000508586 | likely pathogenic | Chronic lymphocytic leukemia | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000427653 | SCV000508587 | likely pathogenic | Adenocarcinoma of stomach | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000434864 | SCV000508588 | likely pathogenic | Transitional cell carcinoma of the bladder | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000417658 | SCV000508589 | likely pathogenic | Renal cell carcinoma, papillary, 1 | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000428396 | SCV000508590 | likely pathogenic | Hepatocellular carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000435583 | SCV000508591 | likely pathogenic | Neoplasm of the large intestine | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000418330 | SCV000508592 | likely pathogenic | Squamous cell lung carcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429028 | SCV000508593 | likely pathogenic | Pancreatic adenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000439733 | SCV000508594 | likely pathogenic | Glioblastoma | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000422504 | SCV000508595 | likely pathogenic | Carcinoma of esophagus | 2016-05-31 | no assertion criteria provided | literature only | |
Database of Curated Mutations |
RCV000429736 | SCV000508596 | likely pathogenic | Ovarian Serous Cystadenocarcinoma | 2016-05-31 | no assertion criteria provided | literature only |