Submissions for variant NM_000455.5(STK11):c.1151G>A (p.Arg384Gln)

gnomAD frequency: 0.00001  dbSNP: rs371102112

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000131727	SCV000186767	uncertain significance	Hereditary cancer-predisposing syndrome	2023-06-22	criteria provided, single submitter	clinical testing	The p.R384Q variant (also known as c.1151G>A), located in coding exon 9 of the STK11 gene, results from a G to A substitution at nucleotide position 1151. The arginine at codon 384 is replaced by glutamine, an amino acid with highly similar properties. This amino acid position is not 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	RCV000465830	SCV000541164	uncertain significance	Peutz-Jeghers syndrome	2022-10-13	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with glutamine, which is neutral and polar, at codon 384 of the STK11 protein (p.Arg384Gln). The frequency data for this variant in the population databases is considered unreliable, as metrics indicate poor data quality at this position in the gnomAD database. 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: 142537). 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.
Color Diagnostics, LLC DBA Color Health	RCV000131727	SCV000686597	uncertain significance	Hereditary cancer-predisposing syndrome	2023-04-11	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 384 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 been identified in 1/240998 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.
Counsyl	RCV000465830	SCV000785798	uncertain significance	Peutz-Jeghers syndrome	2017-12-08	criteria provided, single submitter	clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000986034	SCV001134835	uncertain significance	not provided	2018-11-11	criteria provided, single submitter	clinical testing
GeneDx	RCV000986034	SCV001822266	uncertain significance	not provided	2020-04-06	criteria provided, single submitter	clinical testing	Not observed at a 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
Genome-Nilou Lab	RCV000465830	SCV002057946	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002267881	SCV002552036	uncertain significance	not specified	2024-02-06	criteria provided, single submitter	clinical testing
Myriad Genetics, Inc.	RCV000465830	SCV004018007	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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV002267881	SCV004223098	uncertain significance	not specified	2023-11-22	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1151G>A (p.Arg384Gln) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4.1e-06 in 240998 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1151G>A has been reported in the literature in an individual affected with pancreatic cancer (Yin_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000465830	SCV004818996	uncertain significance	Peutz-Jeghers syndrome	2023-10-02	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with glutamine at codon 384 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 been identified in 1/240998 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000986034	SCV001551283	uncertain significance	not provided		no assertion criteria provided	clinical testing	The STK11 p.Arg384Gln variant was not identified in the literature nor was it identified in Cosmic or LOVD 3.0. The variant was identified in dbSNP (ID: rs371102112) and in ClinVar (classified as VUS for Peutz-Jeghers syndrome by Counsyl and Invitae, and as a VUS for Hereditary cancer-predisposing syndrome by Ambry Genetics and Color). The variant was also identified in control databases in 1 of 240998 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the South Asian population in 1 of 30214 chromosomes (freq: 0.000033); it was not observed in the African, Latino, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish) and Other populations. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. The p.Arg384 residue is not conserved in mammals and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein; however, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is classified as a variant of uncertain significance.