ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.839G>A (p.Arg280Lys) (rs121912660)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000492483 SCV000581118 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-16 criteria provided, single submitter clinical testing The p.R280K variant (also known as c.839G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 839. The arginine at codon 280 is replaced by lysine, an amino acid with highly similar properties. This alteration has been reported in an individual with glioblastoma whose brother was diagnosed with Burkitt's lymphoma (Zhou XP et al. Ann Neurol. 1999 Dec;46(6):913-6). This alteration has also been reported in 1/121 early-onset prostate cancer cases and was not identified in 710 healthy controls (Paulo P et al. PLoS Genet. 2018 04;14(4):e1007355). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity, dominant negative effect, and predicted to affect several p53 isoforms in yeast-based assays (Petitjean A et al. IARC TP53 database [version R17, November 2013]. Hum. Mutat. 2007 Jun;28:622-9; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Malcikova J et al. Biol Chem. 2010 Feb-Mar;391(2-3):197-205; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol. Cell 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). 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.
Invitae RCV000633356 SCV000754578 uncertain significance Li-Fraumeni syndrome 2019-10-15 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 280 of the TP53 protein (p.Arg280Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with glioblastoma and acute lymphoblastic leukemia (PMID: 10589545, 23334668). ClinVar contains an entry for this variant (Variation ID: 376657). Experimental studies have shown that this missense change disrupts the ability of TP53 to bind to DNA and significantly decreases its transcriptional transactivation activity (PMID: 12826609, 20128691, 21343334). 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.
Mendelics RCV000423448 SCV001140249 likely pathogenic Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
Database of Curated Mutations (DoCM) RCV000428952 SCV000509506 likely pathogenic Neoplasm of uterine cervix 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436148 SCV000509507 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418023 SCV000509508 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000428734 SCV000509509 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438568 SCV000509510 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423933 SCV000509511 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431165 SCV000509512 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000440980 SCV000509513 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423739 SCV000509514 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433592 SCV000509515 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000442077 SCV000509516 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000423448 SCV000509517 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000433708 SCV000509518 likely pathogenic Nasopharyngeal Neoplasms 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444610 SCV000509519 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000425366 SCV000509520 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436528 SCV000509521 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000444685 SCV000509522 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only

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