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

gnomAD frequency: 0.00001  dbSNP: rs112431538

Total submissions: 7

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.
Labcorp Genetics (formerly Invitae), Labcorp	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