ClinVar Miner

Submissions for variant NM_000546.6(TP53):c.853G>A (p.Glu285Lys)

gnomAD frequency: 0.00001  dbSNP: rs112431538
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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479542 SCV000568756 pathogenic not provided 2021-07-26 criteria provided, single submitter clinical testing Published functional studies demonstrate a damaging effect: reduced or non-functional transactivation, lack of growth suppression activity (Flaman et al., 1998; Oh et al., 2000; Kato et al., 2003; Dearth et al., 2007; Kotler et al., 2018); Not observed at significant frequency in large population cohorts (Lek et al., 2016); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31105275, 30840781, 29489754, 30720243, 29753700, 15510160, 29979965, 12779080, 22507745, 16337994, 20080630, 7718482, 1459726, 24700732, 17311302, 20190805, 25757734, 19671800, 18348286, 9290701, 10567903, 10987134, 17070499, 9150393, 12792784, 16000567, 9546439, 14559903, 1579447, 17724467, 10761705, 20407015, 16861262, 23624687, 26900293, 24651015, 23894400, 22768918, 1694291)
Ambry Genetics RCV000492206 SCV000581131 pathogenic Hereditary cancer-predisposing syndrome 2021-04-05 criteria provided, single submitter clinical testing The p.E285K (also known as c.853G>A) pathogenic mutation, located in coding exon 7 of the TP53 gene, results from a G to A substitution at nucleotide position 853. The glutamic acid at codon 285 is replaced by lysine, an amino acid with similar properties. The p.E285K variant has been identified in two Chinese families meeting Chompret critera. Both families have a proband with early onset breast cancers and family history of other TP53-related cancers (Lee DS et al. Breast Cancer Res. 2012; 14(2):R66). In addition, this alteration was identified in an individual with three primaries including breast cancer at 38, a leiomyosarcoma at 45, and thyroid cancer at 46 (Mitchell G et al. PLoS ONE. 2013 ; 8(7):e69026). The p.E285K variant is in the DNA binding domain of the TP53 protein and is reported to have loss of transactivation in yeast based assays (IARC TP53 database: Kato S et al. Proc. Natl. Acad. Sci. USA 2003 Jul;100:8424-9). Functional studies have indicated that this is a temperature sensitive alteration that has moderate activity at lower temperatures, and loses transactivation capability at 35 degrees in yeast and 37 degrees in mammalian cells (Grochova D et al. Oncogene 2008 Feb; 27(9):1243-52; Dearth LR et al. Carcinogenesis 2007 Feb; 28(2):289-98; Shiraishi K et al. J. Biol. Chem. 2004 Jan; 279(1):348-55). 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). Another variant at the same position, p.E285V, was also identified as a de novo alteration in a child with both choriod plexus carcinoma and adrenocortical carcinoma by 1.5 years of age (Russell-Swetek A et al. J. Med. Genet. 2008 Sep; 45(9):603-6). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Invitae RCV000633365 SCV000754587 pathogenic Li-Fraumeni syndrome 2022-10-13 criteria provided, single submitter clinical testing 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. ClinVar contains an entry for this variant (Variation ID: 420133). This missense change has been observed in individual(s) with breast cancer and sarcoma (PMID: 11051239, 22507745, 23894400). This variant is not present in population databases (gnomAD no frequency). This sequence change replaces glutamic acid, which is acidic and polar, with lysine, which is basic and polar, at codon 285 of the TP53 protein (p.Glu285Lys). Experimental studies have shown that this missense change affects TP53 function (PMID: 9290701, 12826609, 16861262, 17724467). For these reasons, this variant has been classified as Pathogenic. This variant disrupts the p.Glu285 amino acid residue in TP53. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 12826609, 18762572, 25584008). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing.
Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden RCV000479542 SCV002011125 likely pathogenic not provided 2021-11-03 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV000492206 SCV002582343 likely pathogenic Hereditary cancer-predisposing syndrome 2022-06-18 criteria provided, single submitter clinical testing
Genome-Nilou Lab RCV002289628 SCV002583005 likely pathogenic Li-Fraumeni syndrome 1 2022-06-18 criteria provided, single submitter clinical testing
Oxford Haemato-Oncology Service, Oxford University Hospitals NHS Foundation Trust RCV000626449 SCV000734839 drug response Poly (ADP-Ribose) polymerase inhibitor response 2017-11-27 no assertion criteria provided clinical testing

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