ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.838A>G (p.Arg280Gly) (rs753660142)

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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 RCV000568150 SCV000672409 likely pathogenic Hereditary cancer-predisposing syndrome 2019-11-06 criteria provided, single submitter clinical testing The p.R280G variant (also known as c.838A>G), located in coding exon 7 of the TP53 gene, results from an A to G substitution at nucleotide position 838. The arginine at codon 280 is replaced by glycine, an amino acid with dissimilar properties. This variant was identified in the germline of a woman with pelvic serous carcinoma, and her tumor was found to have loss of heterozygosity (LOH), or loss of the wild type TP53 allele (Xian W et al. J. Pathol. 2010 Jan;220:17-23). This variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation capacity and is predicted to affect several p53 isoforms in yeast based assays (IARC TP53 database; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9; Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9). Studies conducted in human cell lines indicate this alteration is deficient at growth suppression (Kotler E et al. Mol. Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). Based on internal structural analysis, this variant is in direct contact with DNA and is anticipated to result in a significant decrease in binding (Cho Y et al. Science. 1994 Jul;265:346-55). 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 RCV000706131 SCV000835163 uncertain significance Li-Fraumeni syndrome 2020-10-19 criteria provided, single submitter clinical testing This sequence change replaces arginine with glycine at codon 280 of the TP53 protein (p.Arg280Gly). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with B chronic lymphocytic leukemia (PMID: 25587027). ClinVar contains an entry for this variant (Variation ID: 376658). Experimental studies in yeast and cell lines have shown that this missense change impairs the transcriptional transactivation activity of the TP53 protein and displays reduced binding to AP2 (PMID: 12826609, 16288208, 15825182, 12124823). 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.
Database of Curated Mutations (DoCM) RCV000424417 SCV000509540 likely pathogenic Uterine Carcinosarcoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000435565 SCV000509541 likely pathogenic Neoplasm of brain 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000445156 SCV000509542 likely pathogenic Neoplasm of uterine cervix 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000427170 SCV000509543 likely pathogenic Carcinoma of esophagus 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000438255 SCV000509544 likely pathogenic Breast neoplasm 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000420625 SCV000509545 likely pathogenic Squamous cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000426479 SCV000509546 likely pathogenic Adenocarcinoma of stomach 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000436708 SCV000509547 likely pathogenic Lung adenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000419917 SCV000509548 likely pathogenic Malignant melanoma of skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000430194 SCV000509549 likely pathogenic Squamous cell carcinoma of the skin 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439619 SCV000509550 likely pathogenic Acute myeloid leukemia 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000418465 SCV000509551 likely pathogenic Small cell lung carcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000429590 SCV000509552 likely pathogenic Squamous cell carcinoma of the head and neck 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439812 SCV000509553 likely pathogenic Ovarian Serous Cystadenocarcinoma 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000421324 SCV000509554 likely pathogenic Nasopharyngeal Neoplasms 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000431582 SCV000509555 likely pathogenic Transitional cell carcinoma of the bladder 2016-05-31 no assertion criteria provided literature only
Database of Curated Mutations (DoCM) RCV000439157 SCV000509556 likely pathogenic Hepatocellular carcinoma 2016-05-31 no assertion criteria provided literature only
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785300 SCV000923868 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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