ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.1015G>C (p.Glu339Gln) (rs17882252)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ClinGen TP53 Variant Curation Expert Panel,ClinGen RCV000697643 SCV001737935 likely benign Li-Fraumeni syndrome 2020-09-01 reviewed by expert panel curation Transactivation assays show retained function according to Kato, et al. normal tetramer formation according to Kamada et al. and Kawazaki et al., and there is no evidence of a dominant negative effect or loss of function according to Giacomelli, et al. (BS3_Supporting; PMID: 12826609, 30224644, 20978130, 16007150). This variant has been observed in 2-7 60+ year old females without a cancer diagnosis (BS2_Supporting; internal laboratory contributor). In summary, TP53 c.1015G>C (p.E339Q) meets criteria to be classified as likely benign for Li-Fraumeni syndrome. ACMG/AMP criteria applied, as specified by the TP53 Variant Curation Expert Panel: BS3, BS2_Supporting.
Ambry Genetics RCV000130594 SCV000185467 uncertain significance Hereditary cancer-predisposing syndrome 2019-12-18 criteria provided, single submitter clinical testing The p.E339Q variant (also known as c.1015G>C), located in coding exon 9 of the TP53 gene, results from a G to C substitution at nucleotide position 1015. The glutamic acid at codon 339 is replaced by glutamine, an amino acid with highly similar properties. This variant is in the tetramerization domain (TD) of the TP53 protein and was not found to have an effect on oligomerization, transactivation capacity, or a dominant negative effect in yeast based assays (IARC TP53 database; Kato S et al. Proc Natl Acad Sci USA. 2003 Jul 8;100(14):8424-9; Kawaguchi T et al. Oncogene. 2005 Oct 20;24(46):6976-81). Studies conducted in human cell lines indicate this alteration remains proficient at growth suppression (Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). One study which explored the effects of tumor-derived missense mutations on the stability and oligomeric structure of p53 found that the p.E339Q alteration had little to no significant affect on thermal stability of p53TD, but it did alter the electrostatic potential on the surface of p53TD, which could influence interactions with binding partners (Kamada, R et al. J Biol Chem. 2011 Jan 7;286(1):252-8). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
GeneDx RCV000213068 SCV000211766 uncertain significance not provided 2015-04-01 criteria provided, single submitter clinical testing This variant is denoted TP53 c.1015G>C at the cDNA level, p.Glu339Gln (E339Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAG>CAG). Functional analysis of this variant showed that the ability to form stable tetramers was similar to wild type (Kamada 2011). TP53 Glu339Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Glu339Gln occurs at a position that is not conserved across species and is located in the region of interaction with HIPK2 and in the nuclear export signal motif (UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether TP53 Glu339Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000697643 SCV000826267 uncertain significance Li-Fraumeni syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 339 of the TP53 protein (p.Glu339Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with breast cancer (PMID: 28573494). ClinVar contains an entry for this variant (Variation ID: 141893). The Glu339 amino acid falls in the tetramerization domain of the TP53 protein, comprising amino acid residues 325-356 (PMID: 11420672). However, experimental studies have shown that this missense change does not affect the thermal stability, tetramer formation, DNA-binding or transcriptional transactivation activity of the TP53 protein (PMID: 12826609, 20978130, 16007150). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Color Health, Inc RCV000130594 SCV000904077 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-13 criteria provided, single submitter clinical testing

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