Submissions for variant NM_000455.5(STK11):c.463G>A (p.Gly155Arg)

dbSNP: rs763353991

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
GeneDx	RCV000219328	SCV000279822	uncertain significance	not provided	2023-10-03	criteria provided, single submitter	clinical testing	Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Observed in individuals with a personal and family history of breast cancer (Bhai et al., 2021); Published functional studies demonstrate no damaging effect (Donnelly et al., 2021); This variant is associated with the following publications: (PMID: 15863673, 34326862, 34849607)
Ambry Genetics	RCV000572049	SCV000664309	uncertain significance	Hereditary cancer-predisposing syndrome	2023-03-20	criteria provided, single submitter	clinical testing	The p.G155R variant (also known as c.463G>A), located in coding exon 3 of the STK11 gene, results from a G to A substitution at nucleotide position 463. The glycine at codon 155 is replaced by arginine, an amino acid with dissimilar properties. This alteration demonstrated retained autophosphorylation activity in an in vitro kinase assay (Donnelly LL et al. Carcinogenesis, 2021 Dec;42:1428-1438). 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.
Color Diagnostics, LLC DBA Color Health	RCV000572049	SCV000686650	uncertain significance	Hereditary cancer-predisposing syndrome	2020-11-16	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 155 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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.
Invitae	RCV000705698	SCV000834709	uncertain significance	Peutz-Jeghers syndrome	2023-08-31	criteria provided, single submitter	clinical testing	This sequence change replaces glycine, which is neutral and non-polar, with arginine, which is basic and polar, at codon 155 of the STK11 protein (p.Gly155Arg). This variant is not present in population databases (gnomAD no frequency). 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: 234791). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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	RCV000705698	SCV002057799	uncertain significance	Peutz-Jeghers syndrome	2021-07-15	criteria provided, single submitter	clinical testing
Neuberg Centre For Genomic Medicine, NCGM	RCV000705698	SCV004047614	uncertain significance	Peutz-Jeghers syndrome		criteria provided, single submitter	clinical testing	The missense variant p.G155R in STK11 (NM_000455.5) has not been reported previously as a pathogenic variant nor as a benign variant, to our knowledge. is novel (not in any individuals) in gnomAD ExomesThe p.G155R variant is novel (not in any individuals) in 1000 Genomes. There is a moderate physicochemical difference between glycine and arginine. The p.G155R missense variant is predicted to be damaging by both SIFT and PolyPhen2. The glycine residue at codon 155 of STK11 is conserved in all mammalian species. The nucleotide c.463 in STK11 is predicted conserved by GERP++ and PhyloP across 100 vertebrates. For these reasons, this variant has been classified as Uncertain Significance.
Baylor Genetics	RCV003463619	SCV004205567	uncertain significance	Melanoma, cutaneous malignant, susceptibility to, 1	2023-08-18	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV003987458	SCV004803938	uncertain significance	not specified	2024-01-29	criteria provided, single submitter	clinical testing	Variant summary: STK11 c.463G>A (p.Gly155Arg) 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 benign effect of the variant on protein function. In addition, the variant is located close to a splice-site, therefore could also affect splicing: consensus agreement among computation tools predicts no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 2.1e-06 in 1424252 control chromosomes (gnomAD v4). c.463G>A has been reported in the literature in individuals affected with a personal and/or family history of (unspecified) cancer (Bhai_2021). These report(s) do not provide unequivocal conclusions about association of the variant with Peutz-Jeghers Syndrome. At least one publication reports experimental evidence evaluating an impact on protein function and demonstrated no damaging effect for this variant (Donnelly_2021). ClinVar contains an entry for this variant (Variation ID: 234791). Based on the evidence outlined above, the variant was classified as uncertain significance.
All of Us Research Program, National Institutes of Health	RCV000705698	SCV004816363	uncertain significance	Peutz-Jeghers syndrome	2023-09-05	criteria provided, single submitter	clinical testing	This missense variant replaces glycine with arginine at codon 155 of the STK11 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, 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.