Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000444772 | SCV000514798 | likely pathogenic | not provided | 2016-09-30 | criteria provided, single submitter | clinical testing | The D237E variant in the STK11 gene has previously been reported in association with Peutz-Jeghers syndrome (Crocker et al., 2014). The D237E variant was not observed in approximately 6,100 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. The D237E variant is a conservative amino acid substitution, which is not likely to impact secondary protein structure as these residues share similar properties. This substitution occurs at a position that is conserved across species, and in silico analysis predicts this variant is probably damaging to the protein structure/function. Missense variants in nearby residues (S232P, W239G, S240W, G242W, G242E) have been reported in the Human Gene Mutation Database in association with STK11-related disorders (Stenson et al., 2014), supporting the functional importance of this region of the protein. Based on currently available evidence D237E is a strong candidate for a pathogenic variant. However, the possibility that it is benign cannot be excluded. |
| Invitae | RCV003507276 | SCV004261735 | uncertain significance | Peutz-Jeghers syndrome | 2024-01-19 | criteria provided, single submitter | clinical testing | This sequence change replaces aspartic acid, which is acidic and polar, with glutamic acid, which is acidic and polar, at codon 237 of the STK11 protein (p.Asp237Glu). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with STK11-related conditions. ClinVar contains an entry for this variant (Variation ID: 378676). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt STK11 protein function with a positive predictive value of 95%. 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. |