Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000429467 | SCV000629121 | pathogenic | Peutz-Jeghers syndrome | 2022-09-09 | criteria provided, single submitter | clinical testing | ClinVar contains an entry for this variant (Variation ID: 182907). For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects STK11 function (PMID: 9837816, 10441497, 15987703). 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. This missense change has been observed in individuals with Peutz-Jeghers syndrome (PJS) (PMID: 9399902, 9837816, 17924967, 24604241, 24652667). It has also been observed to segregate with disease in related individuals. The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. This sequence change replaces aspartic acid, which is acidic and polar, with asparagine, which is neutral and polar, at codon 176 of the STK11 protein (p.Asp176Asn). |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV000760083 | SCV000889861 | pathogenic | not provided | 2018-03-16 | criteria provided, single submitter | clinical testing | |
| Genome- |
RCV000429467 | SCV002057364 | pathogenic | Peutz-Jeghers syndrome | 2021-07-15 | criteria provided, single submitter | clinical testing | |
| Ambry Genetics | RCV002345554 | SCV002642616 | pathogenic | Hereditary cancer-predisposing syndrome | 2023-09-29 | criteria provided, single submitter | clinical testing | The p.D176N pathogenic mutation (also known as c.526G>A), located in coding exon 4 of the STK11 gene, results from a G to A substitution at nucleotide position 526. The aspartic acid at codon 176 is replaced by asparagine, an amino acid with highly similar properties. This alteration has been reported in several individuals affected with Peutz-Jeghers syndrome (de Leng WW et al. Clin. Genet., 2007 Dec;72:568-73; Yang HR et al. Dig. Dis. Sci., 2010 Dec;55:3458-65; Wang Z et al. Hum. Mutat., 2014 Jul;35:851-8; Dai L et al. Dig. Dis. Sci., 2014 Aug;59:1856-61; Chiang JM et al. Asian J Surg, 2018 Sep;41:480-485), and has been shown to segregate with disease in one family (Mehenni H et al. Am. J. Hum. Genet., 1997 Dec;61:1327-34). Functional studies of this alteration have also demonstrated severely reduced autophosphorylation compared to wild type STK11 in an in vitro protein kinase assay. This alteration also demonstrated subcellular localization similar to wildtype and maintained interaction with PTEN (Mehenni H et al. Am. J. Hum. Genet., 1998 Dec;63:1641-50; Mehenni H et al. Hum. Mol. Genet., 2005 Aug;14:2209-19). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation. |
| Database of Curated Mutations |
RCV000429467 | SCV000510525 | likely pathogenic | Peutz-Jeghers syndrome | 2016-05-13 | no assertion criteria provided | literature only |