ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.842C>A (p.Pro281Gln) (rs121913322)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000213021 SCV000149510 uncertain significance not provided 2016-05-12 criteria provided, single submitter clinical testing This variant is denoted STK11 c.842C>A at the cDNA level, p.Pro281Gln (P281Q) at the protein level, and results in the change of a Proline to a Glutamine (CCG>CAG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Pro281Gln was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Proline and Glutamine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution and is likely to affect protein integrity. STK11 Pro281Gln occurs at a position that is well conserved across species and is located in the protein kinase domain (UniProt). 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 Pro281Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000115601 SCV000185063 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000115601 SCV000292209 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-11 criteria provided, single submitter clinical testing
Invitae RCV000476631 SCV000541131 uncertain significance Peutz-Jeghers syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces proline with glutamine at codon 281 of the STK11 protein (p.Pro281Gln). The proline residue is moderately conserved and there is a moderate physicochemical difference between proline and glutamine. This variant is present in population databases (rs121913322, ExAC 0.04%). This variant has not been reported in the literature in individuals with STK11-related disease. ClinVar contains an entry for this variant (Variation ID: 127705). 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, 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000213021 SCV000888649 uncertain significance not provided 2017-10-18 criteria provided, single submitter clinical testing
Gharavi Laboratory,Columbia University RCV000213021 SCV000920677 uncertain significance not provided 2018-09-16 no assertion criteria provided research

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