ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.717C>G (p.Asn239Lys) (rs1057522275)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000431317 SCV000526938 uncertain significance not provided 2018-03-19 criteria provided, single submitter clinical testing This variant is denoted TP53 c.717C>G at the cDNA level, p.Asn239Lys (N239K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAG). This variant has not, to our knowledge, been published as a germline variant, but has been reported as a somatic variant in oral, renal, and other tumors (Yamakazi 2003, Scott 2012, COSMIC). 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). Additionally, functional studies by Epstein et al. (1998) revealed loss of transactivation as well as a dominant-negative effect. TP53 Asn239Lys was not observed in large population cohorts (Lek 2016). This variant is located in the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Despite some evidence suggesting pathogenicity, based on currently available evidence we consider TP53 Asn239Lys to be a variant of uncertain significance.
Ambry Genetics RCV000492173 SCV000581154 likely pathogenic Hereditary cancer-predisposing syndrome 2017-05-15 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Detected in individual satisfying established diagnostic critera for classic disease without a clear mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Structural Evidence
Invitae RCV000529909 SCV000629858 uncertain significance Li-Fraumeni syndrome 2017-03-19 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 239 of the TP53 protein (p.Asn239Lys). The asparagine residue is highly conserved and there is a moderate physicochemical difference between asparagine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a TP53-related disease. Experimental studies in yeast have shown that this missense change disrupts TP53 transcriptional activity (PMID: 12826609). In summary, this variant is a novel missense change that has been shown to disrupt protein function. However, the available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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