ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.836G>A (p.Gly279Glu) (rs1064793881)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000484876 SCV000567266 pathogenic not provided 2015-07-16 criteria provided, single submitter clinical testing Multiple functional assays have shown G279E to greatly reduce or abolish the transactivation activity of p53(Menendez et al., 2006, Inga et al. 2001, Tsutsumi-Ishii et al., 1995, Campomenosi 2001). The G279Esubstitution was not observed in approximately 6,500 individuals of European and African American ancestry inthe NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. SinceGlycine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. The G279E variant occurs at a position that is conserved, located inthe DNA binding domain, and in regions of interaction with HIPK1, AXIN1, E4F1 and ZNF385A. In silicoanalyses predict that this variant is probably damaging to protein structure and function. Therefore, G279Eis interpreted as a pathogenic variant.
Ambry Genetics RCV000492354 SCV000581126 likely pathogenic Hereditary cancer-predisposing syndrome 2020-02-21 criteria provided, single submitter clinical testing The p.G279E variant (also known as c.836G>A), located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 836. The glycine at codon 279 is replaced by glutamic acid, an amino acid with a few similar properties. <span style="background-color:initial">Per the IARC TP53 Database, this alteration has been reported as a somatic alteration 53 times, however this has not been reported as a germline alteration in any Li-Fraumeni syndrome families (Petitjean A et al. IARC TP53 database [version R16, November 2012]. Hum Mutat. 2007 Jun;28(6):622-9). <span style="background-color:initial">This alteration is located in the functionally critical DNA-binding domain. A number of functional assays in both yeast and mammalian cells have shown this alteration to be devoid of transactivation activity, deficient in the induction of apoptosis, and unable to suppress cell growth after UV irradiation (Kato S et al.Proc Natl Acad Sci USA<span style="background-color:initial">. 2003 Jul 8;100(14):8424-9; Menendez D, Mol. Cell. Biol.<span style="background-color:initial"> 2006 Mar; 26(6):2297-308; <span style="background-color:initial">Inga A, Oncogene 2001 Jan; 20(4):501-13; <span style="background-color:initial">Rokudai Set al. J Biol Chem. 2009 Jan 2;284(1):237-44). <span style="background-color:initial">Additionally, this variant has been shown to exhibit strong dominant negative characteristics (<span style="background-color:initial">Dearth LR, Carcinogenesis 2007 Feb; 28(2):289-98; <span style="background-color:initial">Brachmann RK, Proc. Natl. Acad. Sci. U.S.A. 1996 Apr; 93(9):4091-5<span style="background-color:initial">). Structural analysis indicates that G279 is adjacent to several DNA binding residues, and the p.G279E change creates severe structural perturbations (>15 kcal/mol) resulting in a destabilization of the proper folding of the adjacent loop (internal analysis). 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). <span style="background-color:initial">This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico <span style="background-color:initial">analysis. <span style="background-color:initial">Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Mendelics RCV000989709 SCV001140250 likely pathogenic Squamous cell carcinoma of the head and neck 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000484876 SCV001247046 pathogenic not provided 2019-04-01 criteria provided, single submitter clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000584418 SCV000692066 uncertain significance not specified no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785274 SCV000923842 likely pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research

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