ClinVar Miner

Submissions for variant NM_000455.4(STK11):c.464G>A (p.Gly155Glu) (rs1555737830)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Color RCV000582858 SCV000691510 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-05 criteria provided, single submitter clinical testing
Invitae RCV000757931 SCV000947904 uncertain significance Peutz-Jeghers syndrome 2018-11-01 criteria provided, single submitter clinical testing This sequence change replaces glycine with glutamic acid at codon 155 of the STK11 protein (p.Gly155Glu). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and glutamic acid. This variant also falls at the last nucleotide of exon 3 of the STK11 coding sequence, which is part of the consensus splice site for this exon. 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. Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C15"). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus 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.
University of Washington Department of Laboratory Medicine,University of Washington RCV000757931 SCV000886454 likely benign Peutz-Jeghers syndrome 2018-05-29 criteria provided, single submitter research The STK11 variant designated as NM_000455.4:c.464G>A (p.Gly155Glu) is classified as likely benign. Computer software programs predict that this variant will create a stronger donor site, adding supporting evidence that this variant is benign. Additionally, in one observed family, this variant has been identified in two family members whose skin exams show no evidence of Peutz-Jeghers syndrome. Bayesian analysis integrating all of this data (Tavtigian et al, 2018) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter STK11 function or modify cancer risk. A modest (less than 2-fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.

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