NM_000455.5:c.129_141delCAAGCTCATCGGC

STK11 · NP_000446.1:p.(Lys44SerfsTer3) · NM_000455.5

GRCh37: chr19:1207037 GGGCCAAGCTCATC>G · GRCh38: chr19:1207038 GGGCCAAGCTCATC>G

Gene: STK11 Transcript: NM_000455.5

Final call

Likely Pathogenic

PVS1 very strong PM2 moderate

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.(Lys44SerfsTer3)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000455.5(STK11):c.129_141del is a 13bp frameshift deletion in exon 1 producing p.(Lys44SerfsTer3), predicted to trigger nonsense-mediated decay and complete loss of STK11 protein expression. STK11 loss of function is a well-established mechanism for Peutz-Jeghers syndrome (autosomal dominant).

This variant is absent from gnomAD v2.1 and v4.1 population databases, consistent with a rare pathogenic variant.

The variant has not been reported in ClinVar, COSMIC, or any published patient cohort evaluated in this assessment.

No variant-specific functional studies, segregation data, or de novo observations were identified in the literature. Five OncoKB-curated STK11 publications were reviewed; none mention this variant.

Applying generic ACMG/AMP 2015 classification rules (PMID:25741868): PVS1 (very_strong) + PM2 (moderate) meets the Likely Pathogenic combination threshold (1 Very Strong + 1 Moderate).

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	Met	NM_000455.5(STK11):c.129_141del is a 13bp frameshift deletion in exon 1 (of 9 coding exons) resulting in p.(Lys44SerfsTer3). STK11 loss of function is a well-established disease mechanism for Peutz-Jeghers syndrome (autosomal dominant). The premature termination codon at position 46 occurs well before the last exon-exon junction and is predicted to trigger nonsense-mediated decay, leading to complete absence of the STK11 protein product. Under ClinGen SVI PVS1 recommendations (PMC6185798), full-strength PVS1 is applicable.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 applies to single-nucleotide substitutions at a codon where a different pathogenic amino acid change has been established. This is a 13bp frameshift deletion, not a nucleotide substitution.
PS2	Not met	No de novo observation has been reported for NM_000455.5:c.129_141del. A de novo STK11 frameshift variant (c.698_699insG) has been reported in Peutz-Jeghers syndrome (PMID:22118009) but this is a different variant and does not constitute evidence for the variant under assessment.	pvs1_gene_context
PS3	Not assessed	No variant-specific functional studies were identified for NM_000455.5:c.129_141del in the literature. The five OncoKB-curated papers discuss STK11/LKB1 function or structure at the gene level but do not mention this variant. OncoKB classifies this variant as Likely Oncogenic/Likely Loss-of-function, but this is a computational prediction based on variant type, not experimental functional evidence.	oncokb
PS4	Not assessed	No case-control or prevalence data are available for this variant. The variant is absent from ClinVar and has not been reported in any published patient cohort.	clinvar
PS5	Not met	No reputable germline source has reported this variant as pathogenic. OncoKB classification (Likely Oncogenic) reflects somatic/oncogenic context and is not a germline pathogenicity assertion.	oncokb
PM1	Not met	The variant at codon 44 is located N-terminal to the STK11 kinase domain (approximately residues 49-309). This residue is not in a statistically significant mutational hotspot and does not reside in a well-established critical functional domain with restricted mutational spectrum.
PM2	Met	NM_000455.5:c.129_141del is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes/genomes), consistent with a rare pathogenic variant. Under generic ACMG/AMP rules, absence from large population databases supports a pathogenic interpretation (PM2).	gnomad_v2 gnomad_v4
PM4	N/A	PM4 applies to in-frame deletions/insertions and stop-loss variants that alter protein length without a frameshift. This is an out-of-frame (frameshift) deletion assessed under PVS1.
PM5	N/A	PM5 applies to novel missense variants at a codon where a different pathogenic missense change has been established. This is a frameshift deletion, not a missense variant.
PM6	Not met	No de novo observation has been reported for this variant. Assumed de novo without confirmation of maternity/paternity is not applicable.
PP1	Not assessed	No cosegregation data are available for this variant. No family studies have been reported.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense changes are a common disease mechanism. This is a frameshift deletion.
PP3	N/A	For frameshift/null variants where PVS1 is already applied at full strength, computational evidence of deleterious effect (PP3) is not additive. SpliceAI predicts no significant splice impact (max delta score 0.02), consistent with a variant whose pathogenicity is mediated through protein truncation rather than splicing.	spliceai
PP4	Not assessed	No patient phenotype or family history data were provided for clinical correlation.
PP5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and has not been reported by any diagnostic laboratory.	clinvar
BA1	Not met	NM_000455.5:c.129_141del is absent from gnomAD v2.1 and v4.1. The allele frequency does not exceed the BA1 threshold (>1%).	gnomad_v2 gnomad_v4
BS1	Not met	NM_000455.5:c.129_141del is absent from gnomAD v2.1 and v4.1. The allele frequency does not exceed the BS1 threshold (>0.3%).	gnomad_v2 gnomad_v4
BS2	Not assessed	No observation of this variant in healthy adult individuals has been reported. Absence from gnomAD is consistent with rarity but does not constitute direct observation in a healthy control.
BS3	Not assessed	No variant-specific functional studies demonstrating a benign effect are available for NM_000455.5:c.129_141del.
BS4	Not assessed	No family segregation data are available to evaluate lack of segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. This is a truncating (frameshift) variant.
BP2	Not assessed	No data on observation of this variant in trans with a pathogenic STK11 variant or in cis with a pathogenic variant are available.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions without known function. This is an out-of-frame (frameshift) deletion.
BP4	Not met	Computational evidence does not support a benign interpretation. The variant is a frameshift deletion predicted to produce a truncated protein (p.Lys44SerfsTer3) with complete loss of the kinase domain and C-terminal regulatory regions, consistent with a loss-of-function mechanism. SpliceAI scores are not meaningful for evaluating the protein-level effect of a frameshift.	spliceai
BP5	Not assessed	No data identifying an alternate molecular basis for disease in a patient carrying this variant are available.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants with no predicted splice impact. This is a frameshift deletion, not a synonymous variant.

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