NM_000455.5:c.388G>T

STK11 · NP_000446.1:p.(Glu130Ter) · NM_000455.5

GRCh37: chr19:1219336 G>T · GRCh38: chr19:1219337 G>T

Gene: STK11 Transcript: NM_000455.5

Final call

Pathogenic

PVS1 very strong PM1 moderate PM2 supporting PP3 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.(Glu130Ter)

gnomAD AF

0.0 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000455.5:c.388G>T is a nonsense variant predicted to produce a premature termination codon at position 130 (p.Glu130Ter). This null variant in STK11, a gene where loss of function is a well-established mechanism for Peutz-Jeghers syndrome, meets PVS1 at very strong strength under the ClinGen SVI PVS1 decision framework.

The truncation at codon 130 removes the majority of the protein kinase domain and the entire C-terminal regulatory region of STK11. The kinase domain is a well-characterized critical functional domain essential for LKB1 catalytic activity and tumor suppressor function, satisfying PM1 at moderate strength.

This variant is absent from gnomAD v4.1 with 0 alleles observed across 1,590,826 alleles, meeting the PM2 threshold of <0.1% population frequency.

In silico predictions support a deleterious effect: SpliceAI predicts possible splice impact with a max delta score of 0.52 (acceptor loss), and BayesDel predicts a damaging score of 0.65, satisfying PP3 at supporting strength.

Overall classification: PATHOGENIC. The combination of PVS1 (very strong), PM1 (moderate), PM2 (supporting), and PP3 (supporting) meets the ACMG/AMP 2015 classification threshold for Pathogenic (1 Very Strong + 1 Moderate + >=1 Supporting).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting 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	This variant is a nonsense change (NP_000446.1:p.(Glu130Ter)) predicted to undergo nonsense-mediated decay. STK11 loss of function is an established mechanism for Peutz-Jeghers syndrome. Under the ClinGen SVI PVS1 decision framework (PMC6185798), nonsense variants in genes with an established loss-of-function disease mechanism are assigned PVS1 at very strong strength. The premature termination codon at position 130 lies well upstream of the last exon-exon junction, meeting NMD prediction criteria.	pvs1_generic_framework
PS1	N/A	PS1 applies when the same amino acid change has been established as pathogenic from a different nucleotide change. This is a nonsense variant and PS1 is not applicable to truncating variants.
PS2	Not met	No de novo occurrence of NM_000455.5:c.388G>T has been reported in the available literature or case materials.
PS3	Not met	No variant-specific functional data was identified for NM_000455.5:c.388G>T (p.Glu130Ter) in the seven publications reviewed. The OncoKB-curated literature provides general functional characterization of LKB1/STK11 biology but does not include experimental testing of the E130* variant or systematic range characterization spanning codon 130.
PS4	Not met	No published case-control or case series data confirming this variant in affected individuals was identified. The ClinVar submission (Ambry Genetics, SCV001182975) classifies the variant as Pathogenic based on clinical testing, but no published clinical details or variant-specific case counts are available for independent review. A ClinVar-associated image (PMID:18846624) could not be assessed as no full text or abstract is available.	clinvar
PS5	Not met	PS5 requires the same amino acid change as a previously established pathogenic variant from a different nucleotide change. No alternative nucleotide change creating p.(Glu130Ter) has been reported as pathogenic.
PM1	Met	This variant introduces a premature termination at codon 130 within the protein kinase domain of STK11 (spanning approximately aa49-309). Truncation at this position removes the majority of the kinase domain including subdomains I-XI and the C-terminal regulatory region. The kinase domain of STK11 is a well-characterized critical functional domain essential for LKB1 catalytic activity and tumor suppressor function.	PMID:19892943 PMID:21516316 PMID:24652667
PM2	Met	This variant is absent from gnomAD v4.1 (0/1,590,826 alleles; AF=0.00000%) and absent from gnomAD v2.1. The allele frequency is well below the 0.1% threshold for PM2 application.	gnomad_v4 gnomad_v2
PM5	N/A	PM5 applies to novel missense variants at residues where a different missense change is known to be pathogenic. This is a nonsense variant.
PM6	Not met	No de novo observation of this variant has been reported. PM6 requires a de novo occurrence with or without confirmed maternity and paternity.
PP1	Not met	No cosegregation data is available for this variant.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation where missense variants are a common disease mechanism. This is a nonsense variant.
PP3	Met	In silico tools support a deleterious effect: SpliceAI predicts a possible splice impact with a max delta score of 0.52 (acceptor loss delta 0.52), and BayesDel predicts a damaging effect with a score of 0.65. The SpliceAI prediction reflects potential cryptic splice effects from the nucleotide change beyond the primary nonsense mechanism.	spliceai bayesdel
PP4	Not met	No proband phenotype or family history information is available for assessment. PP4 requires a highly specific patient phenotype or family history for a disease with a single genetic etiology.
PP5	Not met	The ClinVar entry (variation ID 824343) has a review status of 'criteria provided, single submitter,' which is not a 3-star expert panel review. Under the adjudication framework, PP5 is applied at supporting strength only when the ClinVar classification comes from a 3-star expert panel. The ACMG/NSGC referral guideline (PMID:25394175) does not mention this specific variant.	clinvar
BA1	Not met	This variant is absent from gnomAD (0/1,590,826 alleles; AF=0.0). BA1 requires an allele frequency greater than 1% in population databases.	gnomad_v4
BS1	Not met	This variant is absent from gnomAD (0/1,590,826 alleles; AF=0.0). BS1 requires an allele frequency greater than 0.3% in population databases.	gnomad_v4
BS2	Not met	This variant is absent from all population databases. No evidence exists of healthy adult homozygotes or heterozygotes carrying this variant. BS2 requires observation in a healthy adult individual for a fully penetrant disorder.
BS3	Not met	No well-established functional studies demonstrate no deleterious effect for this variant. Available evidence from OncoKB suggests likely loss-of-function, consistent with a pathogenic mechanism rather than a benign one. Reviewed functional literature (structural studies, reviews, TCGA profiling) provides general LKB1 biology context but no variant-specific benign functional data.
BS4	Not met	No cosegregation data is available demonstrating lack of segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes for which primarily truncating variants are known to cause disease. This is a nonsense (truncating) variant.
BP2	Not met	No observation of this variant in trans with a known pathogenic STK11 variant has been reported.
BP4	Not met	Multiple lines of computational evidence suggest a deleterious effect rather than a benign one. SpliceAI predicts possible splice impact (max delta 0.52) and BayesDel predicts a damaging score of 0.65. BP4 requires multiple lines of computational evidence suggesting no impact.	spliceai bayesdel
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease has been reported.
BP6	Not met	The ClinVar classification for this variant is Pathogenic/Likely pathogenic, not benign. BP6 requires a reputable source to classify the variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This is a nonsense variant.
BP3	N/A	BP3 applies to in-frame deletions/insertions in a repetitive region without known function. This is a nonsense substitution.
PM3	N/A	PM3 applies to recessive disorders where a pathogenic variant is detected in trans. STK11-related Peutz-Jeghers syndrome is autosomal dominant.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. This is a nonsense (stop-gain) substitution.

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