Submissions for variant NM_000455.5(STK11):c.25C>G (p.Leu9Val)

dbSNP: rs876661079

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000221102	SCV000279468	uncertain significance	not provided	2021-11-17	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge
Ambry Genetics	RCV001016064	SCV001176976	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	The p.L9V variant (also known as c.25C>G), located in coding exon 1 of the STK11 gene, results from a C to G substitution at nucleotide position 25. The leucine at codon 9 is replaced by valine, an amino acid with highly 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.
Invitae	RCV001046088	SCV001209976	uncertain significance	Peutz-Jeghers syndrome	2023-12-12	criteria provided, single submitter	clinical testing	This sequence change replaces leucine, which is neutral and non-polar, with valine, which is neutral and non-polar, at codon 9 of the STK11 protein (p.Leu9Val). 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: 234549). 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) has been performed at Invitae for this missense variant, however the output from this modeling did not meet the statistical confidence thresholds required to predict the impact of this variant on STK11 protein function. 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.
St. Jude Molecular Pathology, St. Jude Children's Research Hospital	RCV001046088	SCV001737441	uncertain significance	Peutz-Jeghers syndrome	2021-02-25	criteria provided, single submitter	clinical testing	The STK11 c.25C>G (p.Leu9Val) missense change is absent in gnomAD v2.1.1 (PM2_Supporting; https://gnomad.broadinstitute.org/). While five of seven in silico tools predict a benign effect of this variant on protein function, multiple splicing prediction models indicate that this variant may create or strengthen a splice site. Available transcriptional data did not demonstrate abnormal splicing, however the effect of this variant on protein function has not been confirmed by functional assays. To our knowledge, this variant has not been reported in individuals with Peutz-Jeghers syndrome. In summary, this variant meets criteria to be classified as of uncertain significance based on the ACMG/AMP criteria: PM2_Supporting.
Color Diagnostics, LLC DBA Color Health	RCV001016064	SCV002052487	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-14	criteria provided, single submitter	clinical testing	This missense variant replaces leucine with valine at codon 9 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 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.
Genome-Nilou Lab	RCV001046088	SCV002057710	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Fulgent Genetics, Fulgent Genetics	RCV002485442	SCV002785586	uncertain significance	Carcinoma of pancreas; Peutz-Jeghers syndrome; Melanoma, cutaneous malignant, susceptibility to, 1; Germ cell tumor of testis	2021-07-06	criteria provided, single submitter	clinical testing