ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.1163A>G (p.Lys388Arg) (rs756877141)

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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 RCV000569327 SCV000664326 uncertain significance Hereditary cancer-predisposing syndrome 2016-10-31 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000589090 SCV000572303 uncertain significance not provided 2016-11-15 criteria provided, single submitter clinical testing This variant is denoted STK11 c.1163A>G at the cDNA level, p.Lys388Arg (K388R) at the protein level, and results in the change of a Lysine to an Arginine (AAG>AGG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Lys388Arg 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 Arginine share similar properties, this is considered a conservative amino acid substitution. STK11 Lys388Arg occurs at a position that is conserved across species and is located within the C-terminal domain (Hearle 2006). While protein-based in silico analyses are inconsistent regarding the effect this variant may have on protein structure and function, multiple splicing models predict that this variant may result in the gain of a cryptic splice acceptor site; however, the natural splice acceptor site is predicted to be stronger. In the absence of RNA or functional studies, the actual effect of this variant is unknown. Based on currently available evidence, it is unclear whether STK11 Lys388Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589090 SCV000696704 uncertain significance not provided 2016-05-09 criteria provided, single submitter clinical testing Variant summary: The STK11 c.1163A>G (p.Lys388Arg) variant involves the alteration of a conserved nucleotide. 3/4 in silico tools predict a benign outcome (SNPs&GO not captured due to low reliability index). This variant was found in 2/90388 control chromosomes, predominantly observed in the European (Non-Finnish) subpopulation at a frequency of 0.0000394 (2/50760). This frequency is about 6 times the estimated maximal expected allele frequency of a pathogenic STK11 variant (0.0000063), suggesting this is likely a benign polymorphism found primarily in the populations of European (Non-Finnish) origin. The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical diagnostic laboratories; nor evaluated for functional impact by in vivo/vitro studies. Taken together, this variant is classified as VUS - Possibly Benign.
Invitae RCV000543251 SCV000629069 uncertain significance Peutz-Jeghers syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces lysine with arginine at codon 388 of the STK11 protein (p.Lys388Arg). The lysine residue is highly conserved and there is a small physicochemical difference between lysine and arginine. This variant is present in population databases (rs756877141, ExAC 0.004%). This variant has not been reported in the literature in individuals with an STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 422754). 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 and their clinical significance is uncertain. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, this variant has uncertain impact on STK11 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Mendelics RCV000543251 SCV000839428 uncertain significance Peutz-Jeghers syndrome 2018-07-02 criteria provided, single submitter clinical testing

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