ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.538G>A (p.Glu180Lys) (rs879253911)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000544036 SCV001142548 likely pathogenic Li-Fraumeni syndrome 2019-08-28 reviewed by expert panel curation This variant is absent in the gnomAD cohort (PM2_Supporting; http://gnomad.broadinstitute.org). The variant has a BayesDel score > 0.16 and Align GVGD (Zebrafish) is Class 15 or higher (PP3). Transactivation assays show a partially functioning allele according to Kato, et al. and there is evidence of a dominant negative effect and loss of function according to Giacomelli, et al. (PS3_Moderate; PMID: 12826609, 30224644). This variant has been reported in 2 probands meeting Chompret criteria (PS4_Supporting; PMID: 8118819, 25584008). There is a de novo observation of a proband with a diagnosis of an adrenocortical carcinoma without parental confirmation (PM6; PMID: internal expert panel member contributor). In summary, TP53 c.538G>A; p.Glu180Lys meets criteria to be classified as likely pathogenic for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: PM2_Supporting, PP3, PS3_Moderate, PS4_Supporting, PM6.
GeneDx RCV000235571 SCV000292772 likely pathogenic not provided 2018-08-27 criteria provided, single submitter clinical testing This variant is denoted TP53 c.538G>A at the cDNA level, p.Glu180Lys (E180K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has been observed in two children with adrenocortical carcinoma, one of whom was noted to have a family history of Li-Fraumeni-spectrum cancers (Birch 1994, Wasserman 2015). On functional interrogation, this variant has demonstrated reduced protein stability, growth suppression, and apoptotic activities as well as reduced binding to and transactivation of typical p53 response elements (Boyle 1999, Campomenosi 2001, Monti 2002, Malcikova 2010, Schlereth 2010, Monti 2011, Follis 2014, Kotler 2018). Consistent with these findings, TP53 Glu180Lys is reported as having partially functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003). TP53 Glu180Lys was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure/function. Based on currently available information, we consider TP53 Glu180Lys to be a likely pathogenic variant.
Ambry Genetics RCV000492319 SCV000581143 likely pathogenic Hereditary cancer-predisposing syndrome 2019-03-05 criteria provided, single submitter clinical testing The p.E180K variant (also known as c.538G>A), located in coding exon 4 of the TP53 gene, results from a G to A substitution at nucleotide position 538. The glutamic acid at codon 180 is replaced by lysine, an amino acid with similar properties. This alteration was detected in an individual diagnosed with adrenocortical carcinoma at one year of age with family history including early onset breast, bladder, colorectal cancer and glioma (Birch JM et al. Cancer Res. 1994 Mar;54:1298-304). This variant is in the DNA binding domain of the TP53 protein and its position is involved in a dimer-stabilizing salt-bridge (Kitayner M et al. Mol. Cell. 2006 Jun;22:741-53). Multiple functional assays in yeast have shown this variant leads to at least partial deficiency in transactivation activity compared to wild type (Monti P et al. Mol. Cancer Res. 2011 Mar;9:271-9; Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul 8;100(14):8424-9; Campomenosi P et al. Oncogene. 2001 Jun;20:3573-9). This alteration also demonstrated a reduced ability to bind DNA in functional protein microarray studies (Malcikova J et al. Biol. Chem. 391:197-205; Boutell JM et al. Proteomics. 2004 Jul;4:1950-8). Additional studies in human cell lines show this alteration is deficient in cell growth suppression (Kotler E et al. Mol. Cell, 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet., 2018 Oct;50:1381-138). An in vivo assay in mice showed that a functionally equivalent variant (E180R) leads to a reduction in dimerization and DNA binding, and an inability to induce apoptosis (Timofeev O et al. Cell Rep. 2013 May;3:1512-25). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
Invitae RCV000544036 SCV000629836 pathogenic Li-Fraumeni syndrome 2020-06-01 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 180 of the TP53 protein (p.Glu180Lys). 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 observed in individual(s) with Li-Fraumeni syndrome (PMID: 8118819, 17311302, 25584008, Invitae). ClinVar contains an entry for this variant (Variation ID: 245711). This variant has been reported to affect TP53 protein function (PMID: 12826609, 20128691, 20471942, 21343334, 24814347). For these reasons, this variant has been classified as Pathogenic.

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