ClinVar Genomic variation as it relates to human health

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.

This sequence change replaces lysine with glutamine at codon 120 of the TP53 protein (p.Lys120Gln). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamine. This variant is not present in population databases (ExAC no frequency). 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. This variant has been reported to have conflicting or insufficient data to determine the effect on TP53 protein function (PMID: 12826609, 15781620, 27341992, 24219989, 26851285). This variant has not been reported in the literature in individuals with TP53-related conditions. ClinVar contains an entry for this variant (Variation ID: 423255).

The p.K120Q variant (also known as c.358A>C), located in coding exon 3 of the TP53 gene, results from an A to C substitution at nucleotide position 358. The lysine at codon 120 is replaced by glutamine, an amino acid with similar properties. This variant is in the DNA binding domain of the TP53 protein and is reported to have non-functional transactivation in yeast based assays (Kato S et al. Proc. Natl. Acad. Sci. USA. 2003 Jul;100:8424-9). Studies conducted in human cell lines are equivocal about this variant's ability to suppress cell growth (Kotler E et al. Mol.Cell. 2018 Jul;71:178-190.e8; Giacomelli AO et al. Nat. Genet. 2018 Oct;50:1381-1387). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

The TP53 c.358A>C variant is predicted to result in the amino acid substitution p.Lys120Gln. To our knowledge, this variant has not been reported in the literature or in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.