Submissions for variant NM_000455.5(STK11):c.943C>T (p.Pro315Ser)

dbSNP: rs786202431

Total submissions: 4

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165240	SCV000215954	uncertain significance	Hereditary cancer-predisposing syndrome	2021-10-13	criteria provided, single submitter	clinical testing	The p.P315S variant (also known as c.943C>T), located in coding exon 8 of the STK11 gene, results from a C to T substitution at nucleotide position 943. The proline at codon 315 is replaced by serine, an amino acid with similar properties. This alteration is located in the C-terminal non-catalytic region and did not affect the ability of STK11 to assemble into active complexes in one analysis (Zeqiraj E et al. Science, 2009 Dec;326:1707-11). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV001367387	SCV001563735	uncertain significance	Peutz-Jeghers syndrome	2023-04-12	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 185756). This variant has not been reported in the literature in individuals affected with STK11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with serine, which is neutral and polar, at codon 315 of the STK11 protein (p.Pro315Ser). 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. Experimental studies have shown that this missense change does not substantially affect STK11 function (PMID: 19892943). 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 not expected to disrupt STK11 protein function.
Genome-Nilou Lab	RCV001367387	SCV002057879	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001367387	SCV004818939	uncertain significance	Peutz-Jeghers syndrome	2023-05-30	criteria provided, single submitter	clinical testing	This missense variant replaces proline with serine at codon 315 of the STK11 protein. Computational prediction suggests that this variant may not impact protein structure and function (internally defined REVEL score threshold <= 0.5, PMID: 27666373). An experimental functional study demonstrated that this variant did not impair complex formation of a STK11/STRADA/CAB39 heterotrimer or significantly impact the kinase activation of a heterotrimeric AMPK complex (PMID: 19892943). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.