Submissions for variant NM_000455.5(STK11):c.310A>G (p.Arg104Gly)

gnomAD frequency: 0.00002  dbSNP: rs587782783

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000160999	SCV000211709	uncertain significance	not provided	2021-06-17	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 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: 27535533, 15863673)
Invitae	RCV000233314	SCV000284860	uncertain significance	Peutz-Jeghers syndrome	2023-09-22	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. Experimental studies have shown that this missense change does not substantially affect STK11 function (PMID: 34849607). 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. ClinVar contains an entry for this variant (Variation ID: 182905). This variant has not been reported in the literature in individuals affected with STK11-related conditions. This variant is present in population databases (rs587782783, gnomAD 0.004%). This sequence change replaces arginine, which is basic and polar, with glycine, which is neutral and non-polar, at codon 104 of the STK11 protein (p.Arg104Gly).
Counsyl	RCV000233314	SCV000489355	uncertain significance	Peutz-Jeghers syndrome	2016-09-26	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000569641	SCV000664340	likely benign	Hereditary cancer-predisposing syndrome	2023-01-27	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Genome-Nilou Lab	RCV000233314	SCV002057766	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000233314	SCV004017970	uncertain significance	Peutz-Jeghers syndrome	2023-04-13	criteria provided, single submitter	clinical testing	This variant is classified as a variant of uncertain significance as there is insufficient evidence to determine its impact on protein function and/or cancer risk.
PreventionGenetics, part of Exact Sciences	RCV003895077	SCV004711459	uncertain significance	STK11-related disorder	2024-02-22	criteria provided, single submitter	clinical testing	The STK11 c.310A>G variant is predicted to result in the amino acid substitution p.Arg104Gly. To our knowledge, this variant has not been reported in the literature. This variant is reported in 0.0035% of alleles in individuals of European (Non-Finnish) descent in gnomAD and has conflicting interpretations regarding its pathogenicity in Clinvar, ranging from uncertain significance to likely benign (https://www.ncbi.nlm.nih.gov/clinvar/variation/182905/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.