ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.116G>T (p.Arg39Leu) (rs786203250)

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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 RCV000166477 SCV000217275 uncertain significance Hereditary cancer-predisposing syndrome 2018-04-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000166477 SCV000686600 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing
GeneDx RCV000222577 SCV000279174 uncertain significance not provided 2016-10-27 criteria provided, single submitter clinical testing This variant is denoted STK11 c.116G>T at the cDNA level, p.Arg39Leu (R39L) at the protein level, and results in the change of an Arginine to a Leucine (CGC>CTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Arg39Leu was not observed in approximately 6,300 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 Arginine and Leucine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Arg39Leu occurs at a position that is conserved across species and is not located in a known functional domain (Hearle 2006, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether STK11 Arg39Leu is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000780767 SCV000918293 uncertain significance not specified 2018-07-02 criteria provided, single submitter clinical testing Variant summary: STK11 c.116G>T (p.Arg39Leu) results in a non-conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 8.1e-06 in 245434 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.116G>T, has been reported in the literature in individuals affected with Breast Cancer (Tung_2014) and as a somatic event in Colorectal Cancer patients (Betge_2015). 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. Four 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 RCV000204326 SCV000261322 uncertain significance Peutz-Jeghers syndrome 2018-08-06 criteria provided, single submitter clinical testing This sequence change replaces arginine with leucine at codon 39 of the STK11 protein (p.Arg39Leu). The arginine residue is highly conserved and there is a moderate physicochemical difference between arginine and leucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 186826). 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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