ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.1025G>A (p.Arg342Gln) (rs375338359)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000213668 SCV000277448 uncertain significance Hereditary cancer-predisposing syndrome 2019-06-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000478259 SCV000565624 uncertain significance not provided 2018-05-16 criteria provided, single submitter clinical testing This variant is denoted TP53 c.1025G>A at the cDNA level, p.Arg342Gln (R342Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has observed in an individual with breast and/or ovarian cancer (Cast?ra 2014). This variant is reported as having functional transactivation in the International Agency for Research on Cancer TP53 database based on functional assays by Kato et al. (2003), and other functional studies have shown that this variant demonstrates oligomerization, transcription activity, and DNA binding activity similar to wild type (Rollenhagen 1998, Imagawa 2009). TP53 Arg342Gln was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the tetramerization domain and the nuclear export signal (Bode 2004, Zhang 2011, Pessoa 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether TP53 Arg342Gln is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000688863 SCV000816490 uncertain significance Li-Fraumeni syndrome 2018-07-17 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 342 of the TP53 protein (p.Arg342Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs375338359, ExAC 0.01%). This variant has been reported in an individual affected with a personal and/or family history of breast and/or ovarian cancer (PMID: 24549055). ClinVar contains an entry for this variant (Variation ID: 233136). Experimental studies have shown that this missense change results in DNA binding, oligomerization, and transcriptional activity similar to that of wild-type (PMID: 9766574). Additionally, an experimental study in yeast has shown that this variant does not impair the transcriptional transactivation activity of the TP53 protein (PMID: 12826609). The p.Arg342Pro amino acid residue in TP53 has been determined to be clinically significant (PMID: 25226867, 25981898, 16007150, 20978130, 19454241, 19806023, 10064694, 9766574). This suggests that variants that disrupt this residue are likely to be causative of disease. 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.

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