ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.434A>G (p.Glu145Gly) (rs369764220)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000566308 SCV000672323 uncertain significance Hereditary cancer-predisposing syndrome 2016-11-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000566308 SCV000691500 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-24 criteria provided, single submitter clinical testing
Counsyl RCV000123059 SCV000785783 uncertain significance Peutz-Jeghers syndrome 2017-11-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781891 SCV000920277 uncertain significance not specified 2018-03-28 criteria provided, single submitter clinical testing Variant summary: STK11 c.434A>G (p.Glu145Gly) results in a non-conservative amino acid change located in the protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 2e-05 in 51110 control chromosomes (ExAC). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.434A>G in individuals affected with Peutz-Jeghers Syndrome or HBOC and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000123059 SCV000166354 uncertain significance Peutz-Jeghers syndrome 2018-10-04 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glycine at codon 145 of the STK11 protein (p.Glu145Gly). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and glycine. This variant is present in population databases (rs369764220, ExAC <0.01%) but has not been reported in the literature in individuals with a STK11-related disease. ClinVar contains an entry for this variant (Variant ID: 135920). 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 tolerated, but these predictions have not been confirmed by published functional studies. In summary, this variant is a rare missense change that is not predicted to affect protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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