Submissions for variant NM_000455.5(STK11):c.839C>T (p.Pro280Leu)

gnomAD frequency: 0.00001  dbSNP: rs1356762205

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV001017687	SCV001178807	uncertain significance	Hereditary cancer-predisposing syndrome	2022-06-28	criteria provided, single submitter	clinical testing	The p.P280L variant (also known as c.839C>T), located in coding exon 6 of the STK11 gene, results from a C to T substitution at nucleotide position 839. The proline at codon 280 is replaced by leucine, an amino acid with similar properties. This amino acid position is highly 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001199900	SCV001370656	uncertain significance	not specified	2020-05-07	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.839C>T (p.Pro280Leu) results in a non-conservative amino acid change located in the Protein kinase domain (IPR000719) of the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 241804 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.839C>T has been reported in the literature in one individual affected with melanoma (Siroy_2014). The report does 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. One ClinVar submitter (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae	RCV001317877	SCV001508555	uncertain significance	Peutz-Jeghers syndrome	2022-09-01	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 expected to disrupt STK11 protein function. ClinVar contains an entry for this variant (Variation ID: 822377). This variant has not been reported in the literature in individuals affected with STK11-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change replaces proline, which is neutral and non-polar, with leucine, which is neutral and non-polar, at codon 280 of the STK11 protein (p.Pro280Leu).
Genome-Nilou Lab	RCV001317877	SCV002057856	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV001317877	SCV004818921	uncertain significance	Peutz-Jeghers syndrome	2023-06-26	criteria provided, single submitter	clinical testing	This missense variant replaces proline with leucine at codon 280 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 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.