Submissions for variant NM_000455.5(STK11):c.1148G>A (p.Arg383His)

gnomAD frequency: 0.00001  dbSNP: rs730881990

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000235216	SCV000211725	uncertain significance	not provided	2022-11-23	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; Observed in individuals with breast cancer (Tung et al., 2015; Kwong et al., 2020); This variant is associated with the following publications: (PMID: 25186627, 31159747, 28900777, 32068069)
Ambry Genetics	RCV000161013	SCV000214142	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-21	criteria provided, single submitter	clinical testing	The p.R383H variant (also known as c.1148G>A), located in coding exon 9 of the STK11 gene, results from a G to A substitution at nucleotide position 1148. The arginine at codon 383 is replaced by histidine, an amino acid with highly similar properties. This amino acid position is poorly 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.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000204343	SCV000259503	uncertain significance	Peutz-Jeghers syndrome	2024-01-19	criteria provided, single submitter	clinical testing	This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 383 of the STK11 protein (p.Arg383His). 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 missense change has been observed in individual(s) with clinical features of STK11-related conditions (PMID: 31159747). ClinVar contains an entry for this variant (Variation ID: 182918). 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 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.
Color Diagnostics, LLC DBA Color Health	RCV000161013	SCV000686596	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-31	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 383 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 been reported in individuals affected with breast cancer (PMID: 25186627, 32068069). 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.
GeneKor MSA	RCV000161013	SCV000822203	uncertain significance	Hereditary cancer-predisposing syndrome	2018-08-01	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV001197815	SCV001368595	uncertain significance	Carcinoma of pancreas	2018-11-08	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: No criteria apply.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001804887	SCV002051079	uncertain significance	not specified	2021-12-13	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.1148G>A (p.Arg383His) results in a non-conservative amino acid change in the encoded protein sequence. Four 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 241364 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1148G>A has been reported in the literature in individuals affected with breast cancer without evidence for causality or individuals undergoing multigene panel testing for hereditary cancer (examples: Tung_2015, Tsaousis_2019, and Kwong_2020). These reports 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. Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 and all classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Genome-Nilou Lab	RCV000204343	SCV002057945	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Mendelics	RCV001804887	SCV002519415	uncertain significance	not specified	2022-05-04	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV000161013	SCV002531646	uncertain significance	Hereditary cancer-predisposing syndrome	2022-02-26	criteria provided, single submitter	curation
All of Us Research Program, National Institutes of Health	RCV000204343	SCV004818994	uncertain significance	Peutz-Jeghers syndrome	2023-10-30	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with histidine at codon 383 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 been reported in individuals affected with breast cancer (PMID: 25186627, 32068069). 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.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001356849	SCV001552121	uncertain significance	Generalized juvenile polyposis/juvenile polyposis coli		no assertion criteria provided	clinical testing	The STK11 p.Arg383His variant was not identified in the literature nor was it identified in the LOVD 3.0 database. The variant was identified in the following databases: dbSNP (ID: rs730881990) as "With Uncertain significance allele" and in ClinVar (classified as uncertain significance by Invitae, GeneDx, Ambry Genetics and three other submitters). The variant was identified in 1 of 239140 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 107144 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. The p.Arg383 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. 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. 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.