ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.358A>C (p.Lys120Gln) (rs121912658)

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Total submissions: 1
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000478911 SCV000572929 uncertain significance not provided 2017-01-30 criteria provided, single submitter clinical testing This variant is denoted TP53 c.358A>C at the cDNA level, p.Lys120Gln (K120Q) at the protein level, and results in the change of a Lysine to a Glutamine (AAG>CAG). This variant has not, to our knowledge, been published in the literature as either a pathogenic germline variant or a benign polymorphism. However, it has been reported as a somatic variant in a breast carcinoma (Végran 2007). The p53 Lys120 residue is acetylated in response to DNA damage, a process that promotes apoptosis (Sykes 2006). Although TP53 Lys120Gln mimics Lys120 acetylation, apoptotic activity resulting from this variant alone has not been found to differ from wild-type, but was elevated compared to wild-type after exposure to UV radiation (Chang 2013, Yun 2016). While TP53 Lys120Gln is reported as having non-functional transactivation in the International Agency for Research on Cancer TP53 database, other studies have either found normal transactivation or only observed an impact for a few pro-apoptotic targets (Kato 2003, Kakudo 2005, Chang 2013, Monteith 2016, Yun 2016). TP53 Lys120Gln 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 Lysine and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. TP53 Lys120Gln occurs at a position that is conserved 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 currently available evidence, it is unclear whether TP53 Lys120Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.

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