Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000492674 | SCV000580901 | pathogenic | Hereditary cancer-predisposing syndrome | 2017-12-13 | criteria provided, single submitter | clinical testing | The p.N181K pathogenic mutation (also known as c.543C>G), located in coding exon 4 of the STK11 gene, results from a C to G substitution at nucleotide position 543. The asparagine at codon 181 is replaced by lysine, an amino acid with similar properties. This alteration was identified in an individual suspected of having Peutz-Jeghers syndrome (Ambry internal data). Based on an internal structural assessment, this alteration disrupts the Mg-ATP binding in the active site of STK11 (Zeqiraj E et al. Science, 2009 Dec;326:1707-11; Gerlits O et al. Biochemistry, 2013 May;52:3721-7). Three different alterations at the same codon, p.N181Y, p.N181T, and p.N181E, have either been reported in a patient diagnosed with Peutz-Jeghers syndrome (PJS) (Ylikorkala A et al. Hum. Mol. Genet., 1999 Jan;8:45-51) or in patients suspected of having PJS (Connolly DC et al. Am. J. Pathol., 2000 Jan;156:339-45; Amos CI et al. J. Med. Genet., 2004 May;41:327-33). Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Invitae | RCV000819570 | SCV000960237 | pathogenic | Peutz-Jeghers syndrome | 2024-01-28 | criteria provided, single submitter | clinical testing | This sequence change replaces asparagine, which is neutral and polar, with lysine, which is basic and polar, at codon 181 of the STK11 protein (p.Asn181Lys). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individuals with clinical features of Peutz-Jeghers syndrome (Invitae; external communication). ClinVar contains an entry for this variant (Variation ID: 428757). 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%. This variant disrupts the p.Asn181 amino acid residue in STK11. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 9887330, 10623683, 15121768; Invitae). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. For these reasons, this variant has been classified as Pathogenic. |
| Genome- |
RCV000819570 | SCV002057366 | likely pathogenic | Peutz-Jeghers syndrome | 2021-07-15 | criteria provided, single submitter | clinical testing |