ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1069G>A (p.Glu357Lys) (rs759473833)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000563889 SCV000672331 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-01 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000563889 SCV000910058 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-06 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000657031 SCV000232553 uncertain significance not provided 2014-09-30 criteria provided, single submitter clinical testing
GeneDx RCV000657031 SCV000279361 uncertain significance not provided 2017-08-22 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1069G>A at the cDNA level, p.Glu357Lys (E357K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant has not, to our knowledge, been published in the literature as germline pathogenic or benign variant. STK11 Glu357Lys was not observed at a significant allele frequency in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Glu357Lys occurs at a position that is conserved across species and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether STK11 Glu357Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780766 SCV000918290 uncertain significance not specified 2018-06-22 criteria provided, single submitter clinical testing Variant summary: STK11 c.1069G>A (p.Glu357Lys) results in a conservative amino acid change in 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 3.2e-05 in 30914 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1069G>A has been reported in the literature in an individual affected with melanoma (Hamblin_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has 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 RCV000465950 SCV000541158 uncertain significance Peutz-Jeghers syndrome 2018-12-20 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 357 of the STK11 protein (p.Glu357Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs759473833, ExAC 0.007%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 198732). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C55"). 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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