Variant classification summary

NM_000455.4:c.717G>C

STK11 · NP_000446.1:p.(Trp239Cys) · NM_000455.4

GRCh37: chr19:1220699 G>C · GRCh38: chr19:1220700 G>C

Gene: STK11 Transcript: NM_000455.4

Final call

Likely Pathogenic

PS3 moderate PS4 supporting PM1 moderate PM2 supporting PP2 supporting PP3 supporting PP4 supporting PP5 supporting

Variant details

Gene

STK11

Transcript

NM_000455.4

Protein

NP_000446.1:p.(Trp239Cys)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000455.4:c.717G>C (p.Trp239Cys) is a missense variant in STK11 exon 5, within the kinase domain and the critical STRADα-MO25α binding region (residues 239-242).

2

Functional characterization by Boudeau et al. (2004) demonstrated that LKB1 mutations within the 239-242 cluster abolish STRADα-MO25α binding and catalytic activity in a HEK293 co-expression assay, supporting a loss-of-function mechanism (PS3_moderate).

3

The variant is located in a well-established critical functional domain (kinase domain, STRADα-binding cluster) and at a statistically significant cancer hotspot, satisfying PM1 at moderate strength.

4

This variant was identified in a Peutz-Jeghers syndrome proband by Scott et al. (2002), presenting with hamartomatous polyposis diagnosed at age 42, a phenotype highly specific for STK11 (PS4_supporting, PP4_supporting).

5

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, meeting PM2 at supporting strength.

6

STK11 is a tumor suppressor gene with a low rate of benign missense variation, supporting PP2. Multiple in silico predictors (REVEL 0.859) indicate a deleterious effect (PP3). ClinVar reports the variant as Pathogenic with criteria provided by a clinical testing laboratory (PP5).

7

Applying generic ACMG/AMP 2015 combination rules: PS3_moderate + PM1_moderate + PM2_supporting + PP2_supporting + PP3_supporting + PP4_supporting + PP5_supporting + PS4_supporting. This meets the threshold for Pathogenic classification (2 moderate + ≥4 supporting criteria).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	This is a missense variant (p.Trp239Cys), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site). The generic PVS1 framework does not apply to missense substitutions.	pvs1_generic_framework
PS1	Not met	No evidence was identified that a different nucleotide change at this position produces the same amino acid change (p.Trp239Cys) and has been classified as pathogenic. The only reported variant at codon 239 is p.Trp239Gly (c.715T>G) in PMID:20497868, which results in a different amino acid substitution.	PMID:20497868
PS2	Not assessed	No de novo data are available for this variant. Neither the clinical literature nor ClinVar submissions report confirmed de novo occurrence with parental testing.
PS3	Met	Functional characterization by Boudeau et al. (2004, PMID:15561763) demonstrated that LKB1 mutants within the residue 239-242 cluster fail to bind STRADα-MO25α and lose catalytic activity. The study systematically tested 30 LKB1 catalytic domain point mutants in a co-expression/kinase assay in HEK293 cells and identified residues 239-242 as critical for LKB1 complex assembly and activation. While the exact p.Trp239Cys substitution was not individually tested, residue 239 falls within a systematically characterized critical functional cluster.	PMID:15561763
PS4	Met	The variant NM_000455.4:c.717G>C (p.Trp239Cys) was identified in a 42-year-old proband with Peutz-Jeghers syndrome (Scott et al., 2002, PMID:12372054). This single observation provides supporting-level evidence for pathogenicity.	PMID:12372054 clinvar
PS5	Not assessed	PS5 (two or more independent occurrences of a novel variant in affected individuals with a consistent phenotype in the absence of a known pathogenic variant in the gene) is not applicable here. This variant has been reported in ClinVar and in the literature. Formal PS5 counting was not pursued as stronger evidence streams are available.
PM1	Met	The p.Trp239Cys substitution is located within the STK11 kinase domain (codons 50-337) and specifically within the critical STRADα-MO25α binding region (residues 239-242). Functional studies by Boudeau et al. (2004, PMID:15561763) demonstrated that mutations in this cluster abolish LKB1 complex assembly and catalytic activity. Additionally, residue 239 is identified as a statistically significant hotspot in cancerhotspots.org.	PMID:15561763
PM2	Met	This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the PM2 threshold for rare variant absent from population databases (allele frequency < 0.1%).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	A different missense variant at the same codon (p.Trp239Gly, c.715T>G) was reported in a PJS patient by Weng et al. (2010, PMID:20497868), but was classified as a variant of unknown significance. No clearly established pathogenic missense variant at codon 239 with a different amino acid substitution was identified to satisfy PM5 criteria.	PMID:20497868
PM6	Not assessed	No de novo data are available for this variant. No confirmed reports of de novo occurrence with confirmed maternity and paternity testing were identified.
PP1	Not assessed	No segregation data are available for this variant. The proband in PMID:12372054 was a single case without reported family segregation analysis.
PP2	Met	STK11 is a well-established tumor suppressor gene in which missense variants are a recognized mechanism of disease. The gene has a low rate of benign missense variation and a high ratio of pathogenic to benign missense variants, supporting PP2 application for novel missense variants.	clinvar PMID:15561763
PP3	Met	REVEL predicts a damaging effect with a score of 0.859. SpliceAI predicts no significant splice impact (max delta score 0.15). BayesDel score is 0.484. Multiple lines of in silico evidence support a deleterious effect.	revel bayesdel spliceai
PP4	Met	The variant was identified in a patient with clinically confirmed Peutz-Jeghers syndrome (hamartomatous polyposis, mucocutaneous pigmentation), a phenotype highly specific for STK11. The proband in PMID:12372054 presented with hamartomatous intestinal polyps at age 42, consistent with PJS.	PMID:12372054
PP5	Met	This variant has been reported as Pathogenic in ClinVar (variation ID 7458) by a clinical testing laboratory (Labcorp/Invitae), with criteria provided. Although a single submitter without expert panel review limits weight, the clinical classification provides supporting evidence.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the BA1 threshold of 1%.	gnomad_v2 gnomad_v4
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the BS1 threshold of 0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No evidence that this variant has been observed in healthy adult controls in the absence of disease. The variant is absent from gnomAD and was not found in 50 control individuals tested in PMID:12372054.	gnomad_v2 gnomad_v4 PMID:12372054
BS3	Not met	Functional studies do not show a benign effect. Boudeau et al. (2004, PMID:15561763) demonstrated that mutations in the 239-242 cluster abolish STRADα-MO25α binding and catalytic activity, consistent with a loss-of-function mechanism. No well-established functional studies support a benign interpretation.	PMID:15561763
BS4	Not met	No segregation data are available to assess whether the variant fails to segregate with disease. No non-segregation evidence was identified.
BP1	Not met	BP1 applies when a missense variant is found in a gene where only truncating variants cause disease. STK11 has numerous well-documented pathogenic missense variants associated with Peutz-Jeghers syndrome, so BP1 does not apply.	PMID:15561763 PMID:12372054
BP2	Not met	No evidence that this variant has been observed in trans with a known pathogenic STK11 variant. No data are available to assess BP2.
BP4	Not met	Multiple in silico predictors suggest a damaging effect. REVEL score is 0.859 (damaging). There is no in silico evidence supporting a benign interpretation.	revel bayesdel
BP5	Not met	No evidence that an alternate molecular basis for disease has been identified in a case where this variant was found. No data available to assess BP5.
BP6	Not met	This variant has been classified as Pathogenic, not benign, in ClinVar (variation ID 7458). BP6 requires a reputable source to classify the variant as benign or likely benign.	clinvar
BP7	N/A	This is a missense variant (c.717G>C, p.Trp239Cys), not a synonymous variant. BP7 applies only to synonymous variants for which splicing prediction algorithms predict no impact.
BP3	N/A	This is a substitution variant, not an in-frame insertion/deletion. BP3 applies to in-frame indels in non-repeat regions.
PM3	N/A	STK11-associated Peutz-Jeghers syndrome is an autosomal dominant disorder. PM3 applies to recessive disorders where a variant is detected in trans with a pathogenic variant.
PM4	N/A	This is a single-nucleotide substitution (c.717G>C), not a protein-length-altering variant (non-frameshift indel, stop-loss, or initiation codon change). PM4 assesses variants that change protein length.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.