Submissions for variant NM_000455.5(STK11):c.1208A>G (p.Lys403Arg)

gnomAD frequency: 0.00001  dbSNP: rs587781633

Total submissions: 10

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000129742	SCV000184548	likely benign	Hereditary cancer-predisposing syndrome	2020-08-17	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.
Invitae	RCV000228045	SCV000284850	uncertain significance	Peutz-Jeghers syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 403 of the STK11 protein (p.Lys403Arg). This variant is present in population databases (rs587781633, gnomAD 0.003%). 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: 141287). 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. 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.
Counsyl	RCV000228045	SCV000488408	uncertain significance	Peutz-Jeghers syndrome	2016-03-17	criteria provided, single submitter	clinical testing
GeneDx	RCV000478346	SCV000565793	uncertain significance	not provided	2022-04-07	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); 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; This variant is associated with the following publications: (PMID: 27882345)
Color Diagnostics, LLC DBA Color Health	RCV000129742	SCV000911080	likely benign	Hereditary cancer-predisposing syndrome	2015-07-17	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197036	SCV001367671	uncertain significance	Carcinoma of pancreas	2018-11-04	criteria provided, single submitter	clinical testing	This variant was classified as: Uncertain significance. The available evidence on this variant's pathogenicity is insufficient or conflicting. The following ACMG criteria were applied in classifying this variant: BP4.
Genome-Nilou Lab	RCV000228045	SCV002057331	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000228045	SCV004017989	uncertain significance	Peutz-Jeghers syndrome	2023-04-14	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	RCV003415945	SCV004116451	uncertain significance	STK11-related disorder	2023-02-23	criteria provided, single submitter	clinical testing	The STK11 c.1208A>G variant is predicted to result in the amino acid substitution p.Lys403Arg. This variant has been reported in a prostate adenocarcinoma specimen (Table S6, Sholl et al. 2016. PubMed ID: 27882345). This variant is reported in 3 of ~252,000 alleles in gnomAD (http://gnomad.broadinstitute.org/variant/19-1226552-A-G). It has conflicting interpretations of likely benign and uncertain significance in ClinVar (https://preview.ncbi.nlm.nih.gov/clinvar/variation/141287/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414913	SCV000492578	uncertain significance	Breast carcinoma	2016-05-04	no assertion criteria provided	clinical testing