Submissions for variant NM_000455.5(STK11):c.875A>T (p.Tyr292Phe)

dbSNP: rs587780011

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000115602	SCV000149511	uncertain significance	not provided	2014-02-26	criteria provided, single submitter	clinical testing	This variant is denoted STK11 c.875A>T at the cDNA level, p.Tyr292Phe (Y292F) at the protein level, and results in the change of a Tyrosine to a Phenylalanine (TAC>TTC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. STK11 Tyr292Phe was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Tyrosine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution and is likely to affect protein integrity. STK11 Tyr292Phe occurs at a position that is well conserved across species and is located in the Protein Kinase domain (UniProt). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether STK11 Tyr292Phe is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics	RCV000214773	SCV000273899	uncertain significance	Hereditary cancer-predisposing syndrome	2015-02-16	criteria provided, single submitter	clinical testing	The p.Y292F variant (also known as c.875A>T), located in coding exon 7 of the STK11 gene, results from an A to T substitution at nucleotide position 875. The tyrosine at codon 292 is replaced by phenylalanine, an amino acid with highly similar properties. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 5989 samples (11978 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 75,000 alleles tested) in our clinical cohort. Based on protein sequence alignment, this amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of p.Y292F remains unclear.
Invitae	RCV000559287	SCV000629153	uncertain significance	Peutz-Jeghers syndrome	2023-12-31	criteria provided, single submitter	clinical testing	This sequence change replaces tyrosine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 292 of the STK11 protein (p.Tyr292Phe). This variant is present in population databases (rs587780011, 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: 127706). 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.
Genome-Nilou Lab	RCV000559287	SCV002057867	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000559287	SCV004829183	uncertain significance	Peutz-Jeghers syndrome	2023-10-06	criteria provided, single submitter	clinical testing	This missense variant replaces tyrosine with phenylalanine at codon 292 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 2/170906 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.