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
Ambry Genetics RCV000492206 SCV000581131 likely pathogenic Hereditary cancer-predisposing syndrome 2015-10-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Well-characterized mutation at same position,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification
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.
Invitae RCV000633365 SCV000754587 pathogenic Li-Fraumeni syndrome 2017-08-25 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 PARP Inhibitor response 2017-11-27 no assertion criteria provided clinical testing

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