ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.641A>G (p.His214Arg) (rs1057519992)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen 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 (DoCM) RCV000445232 SCV000508586 likely pathogenic Chronic lymphocytic leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427653 SCV000508587 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000434864 SCV000508588 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000417658 SCV000508589 likely pathogenic Renal cell carcinoma, papillary, 1 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428396 SCV000508590 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435583 SCV000508591 likely pathogenic Neoplasm of the large intestine 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418330 SCV000508592 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429028 SCV000508593 likely pathogenic Pancreatic adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439733 SCV000508594 likely pathogenic Glioblastoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000422504 SCV000508595 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429736 SCV000508596 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only

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