Submissions for variant NM_000455.5(STK11):c.1015C>G (p.Pro339Ala)

gnomAD frequency: 0.00001  dbSNP: rs769644352

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000165885	SCV000216636	uncertain significance	Hereditary cancer-predisposing syndrome	2023-08-31	criteria provided, single submitter	clinical testing	The p.P339A variant (also known as c.1015C>G), located in coding exon 8 of the STK11 gene, results from a C to G substitution at nucleotide position 1015. The proline at codon 339 is replaced by alanine, an amino acid with some highly similar properties. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000534169	SCV000629054	uncertain significance	Peutz-Jeghers syndrome	2024-11-13	criteria provided, single submitter	clinical testing	This sequence change replaces proline, which is neutral and non-polar, with alanine, which is neutral and non-polar, at codon 339 of the STK11 protein (p.Pro339Ala). 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: 186311). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt STK11 protein function with a negative predictive value of 95%. 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000781886	SCV000920269	uncertain significance	not specified	2017-11-09	criteria provided, single submitter	clinical testing	Variant summary: The STK11 c.1015C>G (p.Pro339Ala) variant involves the alteration of a conserved nucleotide and 2/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). However, these predictions have yet to be functionally assessed. This variant is absent in 237456 control chromosomes (gnomAD). In addition, a clinical diagnostic laboratory classified this variant as uncertain significance. The variant of interest has not, to our knowledge, been reported in affected individuals via publications. Because of the absence of clinical information and the lack of functional studies, the variant is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Genome-Nilou Lab	RCV000534169	SCV002057898	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000534169	SCV004821585	uncertain significance	Peutz-Jeghers syndrome	2024-07-10	criteria provided, single submitter	clinical testing	This missense variant replaces proline with alanine at codon 339 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 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.
Baylor Genetics	RCV004567286	SCV005052862	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2024-03-27	criteria provided, single submitter	clinical testing
GeneDx	RCV004760411	SCV005371218	uncertain significance	not provided	2023-06-04	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28900777)