ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.853G>A (p.Glu285Lys) (rs112431538)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000479542 SCV000568756 likely pathogenic not provided 2016-11-03 criteria provided, single submitter clinical testing This variant is denoted TP53 c.853G>A at the cDNA level, p.Glu285Lys (E285K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant was observed in an individual meeting Chompret criteria, a child with medulloblastoma, and two individuals with early-onset breast cancer, one of whom had bilateral disease and a similarly affected sister who also shared this variant (Lee 2012, Mitchell 2013, Kool 2014). Functional studies have consistently identified impacts on transactivation, binding specificity, and growth suppression (Scharer 1992, Oh 2000, Dearth 2007, Grochova 2008). Likewise, this variant is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Glu285Lys was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Glu285Lys occurs at a position where amino acids with properties similar to Glutamic Acid are tolerated across species and is located in the DNA binding domain (Bode 2004). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the currently available evidence, we consider TP53 Glu285Lys to be a likely pathogenic variant.
Ambry Genetics RCV000492206 SCV000581131 pathogenic Hereditary cancer-predisposing syndrome 2019-03-28 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 2019-09-16 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 285 of the TP53 protein (p.Glu285Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in individuals affected with breast cancer or adult onset sarcoma (PMID: 22507745, 11051239, 23894400). ClinVar contains an entry for this variant (Variation ID:420133). Experimental studies have shown that this missense change disrupts the transcriptional transactivation function of the TP53 protein in a temperature sensitive manner (PMID: 16861262, 9290701, 17724467, 12826609). A different missense substitution at this codon (p.Glu285Val) has been determined to be pathogenic (PMID: 18762572, 25584008, 12826609). This suggests that the glutamic acid residue is critical for TP53 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
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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