ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.839G>A (p.Arg280Lys)

dbSNP: 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 pathogenic Hereditary cancer-predisposing syndrome 2023-04-03 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). In addition, this alteration was identified in a cohort of women diagnosed with breast cancer before age 30 (Garrett A et al. J Med Genet, 2022 Jun;59:554-558). This variant has been detected in at least one individual at an allele fraction that is suggestive of clonal hematopoiesis, a predictor of TP53 pathogenicity (Ambry internal data; Fortuno C et al. Genet Med. 2022 03;24:673-680). This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression and has no dominant negative effect (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This alteration has been observed numerous times as a somatic mutation in the cancerhotspots.org database (Chang MT et al. Cancer Discov. 2018 02;8:174-183). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000633356 SCV000754578 uncertain significance Li-Fraumeni syndrome 2023-10-19 criteria provided, single submitter clinical testing This sequence change replaces arginine, which is basic and polar, with lysine, which is basic and polar, at codon 280 of the TP53 protein (p.Arg280Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with acute lymphoblastic leukemia, breast cancer, and/or glioblastoma (PMID: 10589545, 23334668; Invitae). ClinVar contains an entry for this variant (Variation ID: 376657). Advanced modeling performed at Invitae incorporating data from internal and/or published experimental studies (PMID: 12826609, 29979965, 30224644) indicates that this missense variant is expected to disrupt TP53 function. Experimental studies have shown that this missense change affects TP53 function (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 neoplasm 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 Gastric adenocarcinoma 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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