Submissions for variant NM_000455.5(STK11):c.1256C>T (p.Ser419Phe)

gnomAD frequency: 0.00001  dbSNP: rs764639416

Total submissions: 7

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000480918	SCV000571779	uncertain significance	not provided	2016-09-26	criteria provided, single submitter	clinical testing	This variant is denoted STK11 c.1256C>T at the cDNA level, p.Ser419Phe (S419F) at the protein level, and results in the change of a Serine to a Phenylalanine (TCC>TTC). This variant has not, to our knowledge, been published in the literature as a germline variant. STK11 Ser419Phe has been reported as a somatic variant in a melanoma patient-derived xenograft (Kemper 2016). This variant was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Serine and Phenylalanine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. STK11 Ser419Phe occurs at a position that is not conserved and is located in the C-terminal domain (Hearle 2006). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether STK11 Ser419Phe is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae	RCV000530692	SCV000629085	uncertain significance	Peutz-Jeghers syndrome	2023-06-24	criteria provided, single submitter	clinical testing	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. 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. ClinVar contains an entry for this variant (Variation ID: 422333). This variant has not been reported in the literature in individuals affected with STK11-related conditions. This variant is present in population databases (rs764639416, gnomAD 0.002%). This sequence change replaces serine, which is neutral and polar, with phenylalanine, which is neutral and non-polar, at codon 419 of the STK11 protein (p.Ser419Phe).
Color Diagnostics, LLC DBA Color Health	RCV001182995	SCV001348639	uncertain significance	Hereditary cancer-predisposing syndrome	2023-11-02	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 419 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 1/163056 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.
Genome-Nilou Lab	RCV000530692	SCV002057997	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Sema4, Sema4	RCV001182995	SCV002531666	uncertain significance	Hereditary cancer-predisposing syndrome	2021-06-11	criteria provided, single submitter	curation
Ambry Genetics	RCV001182995	SCV002678480	uncertain significance	Hereditary cancer-predisposing syndrome	2022-03-24	criteria provided, single submitter	clinical testing	The p.S419F variant (also known as c.1256C>T), located in coding exon 9 of the STK11 gene, results from a C to T substitution at nucleotide position 1256. The serine at codon 419 is replaced by phenylalanine, an amino acid with highly dissimilar properties. This amino acid position is well 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 this alteration remains unclear.
All of Us Research Program, National Institutes of Health	RCV000530692	SCV004819025	uncertain significance	Peutz-Jeghers syndrome	2023-11-20	criteria provided, single submitter	clinical testing	This missense variant replaces serine with phenylalanine at codon 419 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 1/163056 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.