ClinVar Miner

Submissions for variant NM_000546.5(TP53):c.490A>G (p.Lys164Glu) (rs879254249)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000235745 SCV000293963 uncertain significance not provided 2017-12-27 criteria provided, single submitter clinical testing This variant is denoted TP53 c.490A>G at the cDNA level, p.Lys164Glu (K164E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). 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 multiple tumor types including breast, ovarian, liver, head and neck, and leukemia (Lunn1997, Wang 2004, Pekova 2011, Van der Vorst 2012, Saal 2015). A yeast functional study using a head and neck tumor carrying this variant demonstrated deficient transciptional activity, however this tumor also carried another TP53 variant (Van der Vorst 2012). TP53 Lys164Glu 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 Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. TP53 Lys164Glu 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 Lys164Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000541487 SCV000629830 uncertain significance Li-Fraumeni syndrome 2017-07-27 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 164 of the TP53 protein (p.Lys164Glu). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with TP53-related disease. ClinVar contains an entry for this variant (Variation ID: 246416). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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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