ClinVar Miner

Submissions for variant NM_001126112.2(TP53):c.511G>A (p.Glu171Lys) (rs587781845)

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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 RCV000130145 SCV000184979 uncertain significance Hereditary cancer-predisposing syndrome 2016-03-03 criteria provided, single submitter clinical testing Rarity in general population databases (dbsnp, esp, 1000 genomes);Insufficient or conflicting evidence;Other data supporting benign classification
Invitae RCV000168226 SCV000218894 uncertain significance Li-Fraumeni syndrome 2017-09-08 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 171 of the TP53 protein (p.Glu171Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. 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. This sequence change has been reported as somatic in multiple tumor types (http://cancer.sanger.ac.uk/cosmic/mutation/overview?id=44312) including breast tumor tissue (PMID: 9796697, 24330579, 26160192).  The clinical significance of this is unclear. Experimental studies have shown that this missense change partially reduces TP53 protein function (PMID: 12826609). 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.
GeneDx RCV000480730 SCV000571931 uncertain significance not provided 2018-11-19 criteria provided, single submitter clinical testing This variant is denoted TP53 c.511G>A at the cDNA level, p.Glu171Lys (E171K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). TP53 Glu171Lys has not, to our knowledge, been published in the literature as a pathogenic or benign germline variant. 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 retained growth suppression activity in a high-throughput assay (Kotler 2018). TP53 Glu171Lys was not observed in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Bode 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether TP53 Glu171Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.

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