Submissions for variant NM_000455.5(STK11):c.368A>G (p.Gln123Arg)

gnomAD frequency: 0.00004  dbSNP: rs764449808

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001525032	SCV001735028	uncertain significance	Hereditary cancer-predisposing syndrome	2020-12-04	criteria provided, single submitter	clinical testing	This missense variant replaces glutamine with arginine at codon 123 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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 been identified in 5/280426 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001861484	SCV002294312	uncertain significance	Peutz-Jeghers syndrome	2023-01-16	criteria provided, single submitter	clinical testing	This sequence change replaces glutamine, which is neutral and polar, with arginine, which is basic and polar, at codon 123 of the STK11 protein (p.Gln123Arg). This variant is present in population databases (rs764449808, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with STK11-related conditions. This variant is also known as LKB1. ClinVar contains an entry for this variant (Variation ID: 376709). 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. Experimental studies have shown that this missense change does not substantially affect STK11 function (PMID: 19892943). 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.
Ambry Genetics	RCV001525032	SCV005513487	uncertain significance	Hereditary cancer-predisposing syndrome	2024-08-05	criteria provided, single submitter	clinical testing	The p.Q123R variant (also known as c.368A>G), located in coding exon 2 of the STK11 gene, results from an A to G substitution at nucleotide position 368. The glutamine at codon 123 is replaced by arginine, an amino acid with highly similar properties. Functional studies suggest this variant does not significantly disrupt STK11 function; however, additional evidence is needed to confirm these findings (Zeqiraj E et al. Science, 2009 Dec;326:1707-11). 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 available evidence, the clinical significance of this variant remains unclear.