Submissions for variant NM_000455.5(STK11):c.431C>T (p.Pro144Leu)

gnomAD frequency: 0.00001  dbSNP: rs1006375117

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000484471	SCV000572032	uncertain significance	not provided	2016-10-17	criteria provided, single submitter	clinical testing	This variant is denoted STK11 c.431C>T at the cDNA level, p.Pro144Leu (P144L) at the protein level, and results in the change of a Proline to a Leucine (CCG>CTG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Pro144Leu was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Proline and Leucine differ in some properties, this is considered a semi-conservative amino acid substitution. STK11 Pro144Leu occurs at a position that is conserved in mammals and is located in the protein kinase domain and within the site of catalysis (Hearle 2006, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available evidence, it is unclear whether STK11 Pro144Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000704757	SCV000833719	uncertain significance	Peutz-Jeghers syndrome	2023-09-01	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 422535). This variant has not been reported in the literature in individuals affected with STK11-related conditions. 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 proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 144 of the STK11 protein (p.Pro144Leu).
Color Diagnostics, LLC DBA Color Health	RCV001187834	SCV001354721	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-27	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 144 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has been identified in 1/31294 chromosomes 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.
Genome-Nilou Lab	RCV000704757	SCV002057788	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001187834	SCV002633235	uncertain significance	Hereditary cancer-predisposing syndrome	2020-07-15	criteria provided, single submitter	clinical testing	The p.P144L variant (also known as c.431C>T), located in coding exon 3 of the STK11 gene, results from a C to T substitution at nucleotide position 431. The proline at codon 144 is replaced by leucine, an amino acid with similar properties. This amino acid position is 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.
All of Us Research Program, National Institutes of Health	RCV000704757	SCV004816355	uncertain significance	Peutz-Jeghers syndrome	2023-05-16	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 144 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). To our knowledge, functional studies have not been reported for this variant. This variant has not been reported in individuals affected with STK11-related disorders in the literature. This variant has been identified in 1/31294 chromosomes 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.