Submissions for variant NM_000455.5(STK11):c.997C>T (p.Arg333Cys)

dbSNP: rs746564972

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Color Diagnostics, LLC DBA Color Health	RCV001181037	SCV001346097	uncertain significance	Hereditary cancer-predisposing syndrome	2020-03-04	criteria provided, single submitter	clinical testing	This missense variant replaces arginine with cysteine at codon 333 of the STK11 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Splice site prediction tools suggest that this variant may not impact RNA splicing. 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.
Invitae	RCV001202795	SCV001373922	uncertain significance	Peutz-Jeghers syndrome	2021-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces arginine with cysteine at codon 333 of the STK11 protein (p.Arg333Cys). The arginine residue is highly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is present in population databases (rs746564972, ExAC 0.003%). This variant has not been reported in the literature in individuals affected with STK11-related conditions. Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be disruptive. 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	RCV001202795	SCV002057896	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
GeneDx	RCV002254954	SCV002526170	uncertain significance	not provided	2022-06-06	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 28900777)
Ambry Genetics	RCV001181037	SCV002695440	uncertain significance	Hereditary cancer-predisposing syndrome	2023-09-20	criteria provided, single submitter	clinical testing	The p.R333C variant (also known as c.997C>T), located in coding exon 8 of the STK11 gene, results from a C to T substitution at nucleotide position 997. The arginine at codon 333 is replaced by cysteine, an amino acid with highly dissimilar properties. 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 this alteration remains unclear.
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital	RCV002465838	SCV002761028	uncertain significance	not specified	2023-08-15	criteria provided, single submitter	clinical testing