Submissions for variant NM_000455.5(STK11):c.464G>A (p.Gly155Glu)

dbSNP: rs1555737830

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV000582858	SCV000691510	uncertain significance	Hereditary cancer-predisposing syndrome	2023-07-06	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the last nucleotide of exon 3 of the STK11 gene and replaces glycine with glutamic acid at codon 155 of the STK11 protein. Splice site prediction tools suggest that this variant may impact RNA splicing, although this prediction has not been confirmed in published RNA studies. 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 hereditary cancer in the literature. 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.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000757931	SCV000886454	likely benign	Peutz-Jeghers syndrome	2018-05-29	criteria provided, single submitter	research	The STK11 variant designated as NM_000455.4:c.464G>A (p.Gly155Glu) is classified as likely benign. Computer software programs predict that this variant will create a stronger donor site, adding supporting evidence that this variant is benign. Additionally, in one observed family, this variant has been identified in two family members whose skin exams show no evidence of Peutz-Jeghers syndrome. Bayesian analysis integrating all of this data (Tavtigian et al, 2018) gives about 1% probability of pathogenicity, which is consistent with a classification of likely benign. This variant is not predicted to alter STK11 function or modify cancer risk. A modest (less than 2-fold) increase in cancer risk due to this variant cannot be excluded. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000757931	SCV000947904	uncertain significance	Peutz-Jeghers syndrome	2023-10-07	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with glutamic acid, which is acidic and polar, at codon 155 of the STK11 protein (p.Gly155Glu). This variant also falls at the last nucleotide of exon 3, which is part of the consensus splice site for this exon. This variant is not present in population databases (gnomAD no frequency). 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: 492532). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be disruptive. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. 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.
Genome-Nilou Lab	RCV000757931	SCV002057242	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV000582858	SCV002640295	uncertain significance	Hereditary cancer-predisposing syndrome	2024-10-18	criteria provided, single submitter	clinical testing	The p.G155E variant (also known as c.464G>A), located in coding exon 3 of the STK11 gene, results from a G to A substitution at nucleotide position 464. The amino acid change results in glycine to glutamic acid at codon 155, an amino acid with similar properties. This alteration was classified as likely benign by one study that evaluated multiple lines of evidence, including population data, functional evidence, in silico prediction models, segregation with disease and clinical phenotype including tumor characteristics (Tsai GJ et al. Genet Med, 2019 06;21:1435-1442). 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV005000353	SCV005624865	uncertain significance	not provided	2024-10-27	criteria provided, single submitter	clinical testing	The STK11 c.464G>A (p.Gly155Glu) variant has been reported in the published literature in two family members that reportedly show no symptoms of Peutz-Jegher syndrome (PJS) (PMID: 30374176 (2019)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Analysis of this variant using software algorithms for the prediction of the effect of nucleotide changes on splicing yielded predictions that this variant may affect proper STK11 mRNA splicing. Based on the available information, we are unable to determine the clinical significance of this variant.