Submissions for variant NM_000455.5(STK11):c.1250C>G (p.Ala417Gly)

dbSNP: rs1166243253

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000632824	SCV000754020	uncertain significance	Peutz-Jeghers syndrome	2020-11-10	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. 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 tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. This variant has not been reported in the literature in individuals with STK11-related disease. While this variant is not present in population databases, the frequency information is unreliable, as metrics indicate poor data quality at this position in the ExAC database. This sequence change replaces alanine with glycine at codon 417 of the STK11 protein (p.Ala417Gly). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and glycine.
Color Diagnostics, LLC DBA Color Health	RCV001182961	SCV001348575	uncertain significance	Hereditary cancer-predisposing syndrome	2023-12-05	criteria provided, single submitter	clinical testing	This missense variant replaces alanine with glycine at codon 417 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 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.
Genome-Nilou Lab	RCV000632824	SCV002057992	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Ambry Genetics	RCV001182961	SCV002669053	uncertain significance	Hereditary cancer-predisposing syndrome	2019-09-06	criteria provided, single submitter	clinical testing	The p.A417G variant (also known as c.1250C>G), located in coding exon 9 of the STK11 gene, results from a C to G substitution at nucleotide position 1250. The alanine at codon 417 is replaced by glycine, an amino acid with similar properties. This amino acid position is poorly 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.
GenomeConnect - Invitae Patient Insights Network	RCV000632824	SCV004228676	not provided	Peutz-Jeghers syndrome		no assertion provided	phenotyping only	Variant interpreted as Uncertain significance and reported on 02-13-2020 by Lab Invitae. GenomeConnect-Invitae Patient Insights Network assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. Registry team members make no attempt to reinterpret the clinical significance of the variant. Phenotypic details are available under supporting information.