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STK11c.911G>AUncertain significance
Print report
Variant interpretation report

STK11 c.911G>A, p.(Arg304Gln)

NM_000455.5:c.911G>A NP_000446.1:p.(Arg304Gln) Missense · exon 7 View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About STK11

STK11 encodes a serine/threonine kinase that acts as a tumor suppressor, regulating cell polarity, energy metabolism, and stress responses through the AMPK signaling pathway. Germline mutations in this gene cause Peutz-Jeghers syndrome, an inherited condition marked by gastrointestinal polyps, mucocutaneous pigmentation, and an elevated risk of several cancers. Loss of STK11 function also occurs in cancers of the lung, pancreas, breast, cervix, liver, and other tissues, where it promotes tumor growth.

NCBI Gene ↗ OncoKB ↗
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

Met at supporting: gnomAD v4.1 all-comers AF 1.84625e-05 is below the generic PM2 threshold of 0.0001, with zero homozygotes.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

VUS: PM2 at supporting strength is the only applied criterion, which does not meet generic ACMG/AMP thresholds for a definitive pathogenic or benign classification.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

gnomAD v4.1
gnomAD v2.1
Population frequency
29 / 1,570,750 alleles

gnomAD v4.1: 29 / 1,570,750 alleles. Recorded AF 1.84625e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.8716e-05; MAF= 0.00387%, 7/180804 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000183666; MAF= 0.01837%, 3/16334 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.567 recorded score

Recorded REVEL score: 0.567. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied
ClinVar submissions
12 reported laboratory submissions

10 Uncertain significance · 1 Likely benign · 1 Uncertain Significance. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. STK11, a tumor suppressor and intracellular kinase, is frequently mutated in lung cancer.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV109429977, n = 1 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

28 criteria with recorded statuses: 1 met · 7 not met · 15 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

No applicable STK11 VCEP or gene-specific population framework was available, so the supplied generic thresholds were used.

BA1 and BS1 are not met because the observed all-comers and ancestry-specific population frequencies are far below their thresholds.

BS2 is not met because no homozygotes are observed in the available gnomAD datasets.

PM2 is met at supporting strength using the default all-comers gnomAD frequencies, which are below 0.0001; non-cancer subset data independently support rarity.

Met · 1

PM2 SupportingMet at supporting: gnomAD v4.1 all-comers AF 1.84625e-05 is below the generic PM2 threshold of 0.0001, with zero homozygotes. Details ▾Hide ▴
Reasoning

No governing STK11 VCEP or gene-specific framework was available, so the supplied generic PM2 supporting threshold of allele frequency <=0.0001 applies. Using the default all-comers population sources, the variant has AF 3.8716e-05 in gnomAD v2.1 and 1.84625e-05 in gnomAD v4.1, both below 0.0001, with zero homozygotes in each dataset. The v4.1 group maximum FAF is 2.579e-05. Non-cancer subsets independently remain below the threshold, with AF 4.02706e-05 in v2.1 non-cancer exomes and 2.70314e-05 in v3.1 non-cancer genomes.

Rule
Generic PM2: allele frequency <=0.0001 at supporting strength; use all-comers gnomAD totals absent a governing VCEP specification.
Evidence considered
  • No applicable STK11-specific VCEP specification was identified; the supplied generic PM2 threshold is allele frequency <=0.0001 at supporting strength.
  • Default all-comers source, gnomAD v2.1 exomes: AF 3.871595761155727e-05 (7/180804), 0 homozygotes.
  • Default all-comers source, gnomAD v4.1 exomes plus genomes: AF 1.8462517905459174e-05 (29/1570750), 0 homozygotes, and group maximum FAF 2.579e-05.
  • The observed highest ancestry-specific frequencies are 0.00018366597281743602 in v2.1 Finnish and 0.0001656726308813784 in v4.1 Middle Eastern individuals; these are noted as small-subgroup observations, while the supplied default rule directs use of all-comers totals absent a governing specification.
  • Non-cancer subsets corroborate rarity: gnomAD v2.1 non-cancer exomes AF 4.027061855670103e-05 and gnomAD v3.1 non-cancer genomes AF 2.703141049899984e-05, both with 0 homozygotes.
  • The ACMG/AMP standards publication is the named source for the generic population-frequency framework (PMID:25741868).
Sources
gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗

Not met · 7 · evaluated, threshold not reached

PP3 Not met: REVEL 0.567 is below the supporting PP3 threshold of 0.644 for missense variants. Details ▾Hide ▴
Reasoning

The variant is missense (NP_000446.1:p.(Arg304Gln)), so PP3 is evaluated using REVEL only; SpliceAI is not applicable to this missense protein-impact assessment. REVEL is 0.567, below the generic ClinGen SVI supporting PP3 threshold of >=0.644 from the supplied Pejaver et al. 2022 calibration (PMID:36413997), so PP3 is not met. BayesDel is not used because no generic ACMG-strength calibration is established.

Evidence considered
  • The normalized consequence is missense, p.(Arg304Gln), selecting the REVEL path and excluding SpliceAI for PP3/BP4.
  • REVEL score is 0.567; the supplied ClinGen SVI calibration assigns supporting PP3 at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997).
  • BayesDel is not used because the supplied rules state that no generic ACMG-strength calibration is established.
Sources
revel
PP5 Not met: the exact ClinVar record has zero expert-panel submissions and no expert-panel Pathogenic or Likely pathogenic classification. Details ▾Hide ▴
Reasoning

PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. The exact ClinVar record for NM_000455.5:c.911G>A (p.Arg304Gln) has zero expert-panel submissions and reports conflicting single-submitter laboratory classifications, principally Uncertain significance, with one Likely benign submission. Ordinary laboratory submissions and aggregate labels do not trigger PP5.

Rule
PP5 met only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; no such expert-panel classification is present.
Evidence considered
  • The exact ClinVar record reports expert_panel_submissions: 0 and review status criteria provided, single submitter.
  • The exact-variant submissions are laboratory assertions, including Uncertain significance and one Likely benign assertion; these are not expert-panel classifications and cannot trigger PP5.
  • PMID:23788249 and PMID:25356965 are general ACMG policy papers and do not provide an expert-panel classification for this exact variant.
Sources
clinvar ↗PMID:23788249 ↗PMID:25356965 ↗
BA1 Not met: all-comers gnomAD v4.1 AF 1.84625e-05 is far below the generic BA1 threshold of 0.05. Details ▾Hide ▴
Reasoning

No governing STK11 VCEP or gene-specific framework was available, so the supplied generic ACMG/AMP BA1 threshold of allele frequency >=0.05 applies. The variant's all-comers frequency is 3.8716e-05 (7/180804) in gnomAD v2.1 and 1.84625e-05 (29/1570750) in gnomAD v4.1, far below 0.05. The highest observed ancestry-specific frequencies are also far below the threshold: 0.000183666 in v2.1 Finnish and 0.000165673 in v4.1 Middle Eastern individuals. The non-cancer subsets are similarly rare, at 4.02706e-05 in gnomAD v2.1 non-cancer exomes and 2.70314e-05 in gnomAD v3.1 non-cancer genomes.

Rule
Generic BA1: allele frequency >=0.05; no governing VCEP specification available.
Evidence considered
  • No applicable STK11-specific VCEP specification was identified; the supplied generic ACMG/AMP BA1 threshold is allele frequency >=0.05.
  • gnomAD v2.1 all-comers exomes: 7/180804 alleles, AF 3.871595761155727e-05, with 0 homozygotes; highest reported subpopulation AF was 0.00018366597281743602 in Finnish individuals.
  • gnomAD v4.1 all-comers exomes plus genomes: 29/1570750 alleles, AF 1.8462517905459174e-05, with 0 homozygotes; highest reported subpopulation AF was 0.0001656726308813784 in Middle Eastern individuals.
  • The available non-cancer subsets do not approach BA1: gnomAD v2.1 non-cancer exomes AF 4.027061855670103e-05 and gnomAD v3.1 non-cancer genomes AF 2.703141049899984e-05.
  • The ACMG/AMP standards publication describes the general population-frequency evidence framework used here (PMID:25741868).
Sources
gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗
BS1 Not met: the highest observed gnomAD ancestry-specific AF, 0.000183666, remains below the generic BS1 threshold of 0.01. Details ▾Hide ▴
Reasoning

No governing STK11 VCEP or gene-specific framework was available, so the supplied generic BS1 threshold of allele frequency >=0.01 applies. The all-comers frequency is 3.8716e-05 in gnomAD v2.1 and 1.84625e-05 in gnomAD v4.1, both substantially below 0.01. The highest observed ancestry-specific frequencies, 0.000183666 in v2.1 Finnish and 0.000165673 in v4.1 Middle Eastern individuals, also remain below the threshold. Non-cancer subset frequencies are likewise below 0.01.

Rule
Generic BS1: allele frequency >=0.01; no governing VCEP specification available.
Evidence considered
  • No applicable STK11-specific VCEP specification was identified; the supplied generic BS1 threshold is allele frequency >=0.01.
  • gnomAD v2.1 all-comers exomes: AF 3.871595761155727e-05 (7/180804); highest reported subpopulation AF 0.00018366597281743602 in Finnish individuals.
  • gnomAD v4.1 all-comers exomes plus genomes: AF 1.8462517905459174e-05 (29/1570750); highest reported subpopulation AF 0.0001656726308813784 in Middle Eastern individuals.
  • Non-cancer frequencies are also below the BS1 threshold: 4.027061855670103e-05 in gnomAD v2.1 non-cancer exomes and 2.703141049899984e-05 in gnomAD v3.1 non-cancer genomes.
  • The ACMG/AMP standards publication provides the general population-frequency criterion framework used here (PMID:25741868).
Sources
gnomad_v2 ↗gnomad_v4 ↗PMID:25741868 ↗
BS2 Not met: gnomAD v2.1 and v4.1 each report 0 homozygotes, so no healthy-homozygote evidence supports BS2. Details ▾Hide ▴
Reasoning

BS2 requires observation of the variant in healthy adults, typically including homozygotes where compatible with the disease mechanism. The available gnomAD data show zero homozygotes in gnomAD v2.1, gnomAD v4.1, gnomAD v2.1 non-cancer exomes, and gnomAD v3.1 non-cancer genomes. These population observations therefore do not provide BS2 evidence.

Rule
BS2 requires variant observation in healthy adults, with homozygote observation particularly informative when compatible with the disorder; zero observed homozygotes does not meet BS2.
Evidence considered
  • gnomAD v2.1 all-comers exomes report 0 homozygotes among 7 variant alleles.
  • gnomAD v4.1 all-comers exomes plus genomes report 0 homozygotes among 29 variant alleles.
  • The available non-cancer subsets also report 0 homozygotes: gnomAD v2.1 non-cancer exomes and gnomAD v3.1 non-cancer genomes.
  • No independent healthy-adult cohort or disease-penetrance study documenting homozygous carriers was identified in the supplied case evidence.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 Not met: REVEL 0.567 exceeds the supporting BP4 threshold of 0.29 for missense variants. Details ▾Hide ▴
Reasoning

The variant is missense (NP_000446.1:p.(Arg304Gln)), so BP4 is evaluated using REVEL only; the SpliceAI score cannot provide benign support for a missense variant. REVEL is 0.567, above the generic ClinGen SVI supporting BP4 threshold of <=0.29 from the supplied Pejaver et al. 2022 calibration (PMID:36413997), placing it in the non-benign-supporting gray zone; therefore BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established.

Evidence considered
  • The normalized consequence is missense, p.(Arg304Gln), selecting the REVEL path and excluding SpliceAI for PP3/BP4.
  • REVEL score is 0.567; the supplied ClinGen SVI calibration assigns supporting BP4 at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997).
  • The REVEL result is intermediate rather than benign-supporting, and does not authorize substitution of the SpliceAI score.
  • BayesDel is not used because the supplied rules state that no generic ACMG-strength calibration is established.
Sources
revel
BP6 Not met: one ordinary laboratory submission is Likely benign, but the exact ClinVar record has zero expert-panel submissions. Details ▾Hide ▴
Reasoning

BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. The exact ClinVar record for NM_000455.5:c.911G>A (p.Arg304Gln) has zero expert-panel submissions. Although one ordinary laboratory submission is Likely benign, ordinary submissions and aggregate ClinVar labels are explicitly insufficient to trigger BP6.

Rule
BP6 met only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; no such expert-panel classification is present.
Evidence considered
  • The exact ClinVar record reports expert_panel_submissions: 0.
  • The record includes one Likely benign single-submitter laboratory assertion, but it is not an expert-panel classification and cannot trigger BP6.
  • The aggregate ClinVar classification is conflicting and is not eligible evidence for BP6 under the specified rule.
Sources
clinvar ↗

Not assessed · 15 · no assessment recorded

PS1 PS1 could not be assessed because its agent did not produce valid output. Details ▾Hide ▴
Still missing
  • attempt 1: evidence_refs must contain only source_registry keys
  • attempt 2: evidence_refs must contain only source_registry keys
  • attempt 3: evidence_refs must contain only source_registry keys
PS2 Not assessed: no parental testing or confirmed de novo observation is documented for the present c.911G>A (p.Arg304Gln) variant. Details ▾Hide ▴
Reasoning

No case-specific evidence establishes that NM_000455.5:c.911G>A (p.Arg304Gln) arose de novo in an affected proband. The available de novo STK11 publication concerns a different variant, c.698_699insG (p.Phe234Leufs*3), in a child with clinically unaffected parents; that observation cannot be transferred to c.911G>A. Parental genotypes for the present variant and confirmed maternity/paternity are not documented.

Rule
Generic ACMG/AMP PS2 requires a confirmed de novo occurrence in an affected individual with confirmed maternity and paternity; no variant-specific de novo evidence is available.
Evidence considered
  • The case materials do not document parental testing or a de novo result for NM_000455.5:c.911G>A (p.Arg304Gln).
  • The available publication PMID:22118009 reports de novo STK11 c.698_699insG (p.Phe234Leufs*3) in a different child and therefore is not variant-specific evidence for c.911G>A.
Still missing
  • Case-specific proband phenotype and molecular report
  • Maternal and paternal genotypes for c.911G>A
  • Confirmed maternity and paternity
  • Assessment for parental mosaicism
PS3 Not assessed: no validated functional assay tested the exact R304Q variant, while available assays studied different STK11 substitutions such as R304W. Details ▾Hide ▴
Reasoning

No applicable STK11 VCEP or gene-specific framework was available, so generic ACMG/AMP functional-evidence guidance applies. The exact variant NM_000455.5:c.911G>A (NP_000446.1:p.Arg304Gln; R304Q) was not functionally tested in the reviewed literature. PMID:12552571 tested the different same-residue substitution R304W, reporting absent autophosphorylation and p53 phosphorylation, altered localization, and failure to suppress G361 cell growth; PMID:17404884 likewise reports functional results for other STK11 variants, including R304W, not R304Q; PMID:9837816 tested D176N, W308C, L67P, and K78I, not R304Q. Results from a different amino-acid substitution or other variants cannot be assigned directly to R304Q, and no validated assay result for the exact variant was found. Therefore PS3 cannot be applied at any strength.

Evidence considered
  • PMID:12552571 tested R304W rather than R304Q; the reported loss of autophosphorylation, loss of p53 phosphorylation, altered localization, and failure to suppress G361 cell growth therefore cannot be directly assigned to the case variant.
  • PMID:17404884 reports STK11 functional results for other variants, including R304W, but does not test R304Q.
  • PMID:9837816 reports reduced autophosphorylation for D176N, W308C, L67P, and K78I, none of which is R304Q.
Still missing
  • A validated functional assay directly testing STK11 p.Arg304Gln/R304Q is needed.
  • Assay controls, biological relevance, and quantitative calibration for the exact variant are unavailable.
Sources
PMID:12552571 ↗PMID:17404884 ↗PMID:9837816 ↗
PS4 Not assessed: no exact-variant case-control counts, enrichment statistic, odds ratio, or affected-case versus control comparison is available. Details ▾Hide ▴
Reasoning

No exact-variant case-control enrichment analysis, affected-case count, odds ratio, or statistically interpretable phenotype prevalence comparison was identified. The literature extracts report other STK11 variants or gene-level Peutz-Jeghers syndrome information, not c.911G>A/p.Arg304Gln in affected cases versus controls. Therefore PS4 cannot be assessed.

Rule
Generic ACMG/AMP PS4 requires statistically significant enrichment of the variant in affected individuals compared with controls; no exact-variant enrichment statistic is available.
Evidence considered
  • The exact ClinVar record is for NM_000455.5:c.911G>A (p.Arg304Gln), but its submissions do not provide a case-control enrichment analysis.
  • PMID:12552571 and PMID:17404884 discuss other STK11 variants and/or gene-level Peutz-Jeghers syndrome findings, not this exact variant in an affected-case/control comparison.
Still missing
  • Exact-variant affected-case and control counts or a validated case-control enrichment statistic are unavailable.
  • No applicable STK11 VCEP PS4 rule or threshold was retrieved.
Sources
clinvar ↗PMID:12552571 ↗PMID:17404884 ↗
PM1 PM1 could not be assessed because its agent did not produce valid output. Details ▾Hide ▴
Still missing
  • attempt 1: evidence_refs must contain only source_registry keys
  • attempt 2: evidence_refs must contain only source_registry keys
  • attempt 3: evidence_refs must contain only source_registry keys
PM5 PM5 could not be assessed because its agent did not produce valid output. Details ▾Hide ▴
Still missing
  • attempt 1: evidence_refs must contain only source_registry keys
  • attempt 2: evidence_refs must contain only source_registry keys
  • attempt 3: evidence_refs must contain only source_registry keys
PM6 Not assessed: no apparently de novo occurrence is reported for c.911G>A (p.Arg304Gln), and parental testing is unavailable. Details ▾Hide ▴
Reasoning

No case-specific evidence establishes that NM_000455.5:c.911G>A (p.Arg304Gln) is apparently de novo. The only identified de novo STK11 report concerns c.698_699insG (p.Phe234Leufs*3), not the present variant, and cannot support PM6 for c.911G>A. There is no documented parental testing, maternity/paternity confirmation, or proband-level report for this variant.

Rule
Generic ACMG/AMP PM6 requires a variant appearing apparently de novo in an affected individual without confirmed maternity and paternity; no variant-specific observation is available.
Evidence considered
  • No parental or proband-level evidence for NM_000455.5:c.911G>A (p.Arg304Gln) is present in the reviewed case materials.
  • PMID:22118009 describes an apparently de novo different STK11 variant, c.698_699insG (p.Phe234Leufs*3), and is not applicable to this variant.
Still missing
  • Case-specific proband report
  • Maternal and paternal testing
  • Confirmed maternity and paternity
  • Independent confirmation of the variant in the proband
PP1 Not assessed: zero informative meioses or affected relatives carrying c.911G>A (p.Arg304Gln) are documented. Details ▾Hide ▴
Reasoning

No affected relatives carrying NM_000455.5:c.911G>A (p.Arg304Gln), informative meioses, or family-level segregation data are documented. Reports of other STK11 variants or gene-level Peutz-Jeghers syndrome families do not establish segregation of the present variant and cannot be used for PP1.

Rule
Generic ACMG/AMP PP1 requires co-segregation of the variant with disease in affected family members; no informative family segregation is available.
Evidence considered
  • The case materials contain no family pedigree, affected-relative genotypes, informative meioses, or segregation observations for NM_000455.5:c.911G>A (p.Arg304Gln).
  • The reviewed STK11 family literature concerns other variants and therefore cannot provide segregation evidence for c.911G>A.
Still missing
  • Pedigree with phenotypes and relationships
  • Genotypes of affected relatives
  • Number of informative meioses
  • Phenotype consistency among carriers
PP2 PP2 could not be assessed because its agent did not produce valid output. Details ▾Hide ▴
Still missing
  • attempt 1: evidence_refs must contain only source_registry keys
  • attempt 2: evidence_refs must contain only source_registry keys
  • attempt 3: evidence_refs must contain only source_registry keys
PP4 Not assessed: no patient phenotype or phenotype-specific diagnostic findings are documented for comparison with an STK11-related disorder. Details ▾Hide ▴
Reasoning

The available record does not provide the patient's phenotype, clinical diagnostic findings, or a phenotype-specific assessment for Peutz-Jeghers syndrome or another STK11-related disorder. General descriptions of Peutz-Jeghers syndrome in the literature cannot be assigned to this individual variant case. Therefore PP4 cannot be assessed.

Rule
Generic ACMG/AMP PP4 requires a patient's phenotype or family history highly specific for a disease with a single-gene etiology; no individual phenotype is available.
Evidence considered
  • The case record identifies the exact variant and lists Peutz-Jeghers syndrome among ClinVar conditions, but does not document this patient's phenotype or diagnostic findings.
  • General Peutz-Jeghers syndrome descriptions in the reviewed literature are not evidence that this individual has a highly specific phenotype.
Still missing
  • Individual clinical phenotype and diagnostic findings are unavailable.
  • No applicable STK11 VCEP PP4 specification was retrieved.
Sources
clinvar ↗PMID:17404884 ↗
BS3 Not assessed: no validated benign functional assay tested exact STK11 R304Q with evidence of preserved biologically relevant function. Details ▾Hide ▴
Reasoning

No applicable STK11 VCEP or gene-specific framework was available, so generic ACMG/AMP functional-evidence guidance applies. The reviewed literature contains no validated benign functional assay for the exact variant NM_000455.5:c.911G>A (NP_000446.1:p.Arg304Gln; R304Q). PMID:12552571 and PMID:17404884 evaluated other STK11 variants, including R304W, and PMID:9837816 evaluated D176N, W308C, L67P, and K78I. These studies do not demonstrate that R304Q preserves a well-established, biologically relevant function with appropriate controls, so BS3 cannot be applied at any strength.

Evidence considered
  • The reviewed functional studies do not test R304Q: PMID:12552571 and PMID:17404884 test other variants including R304W, while PMID:9837816 tests D176N, W308C, L67P, and K78I.
  • Because no exact-variant assay demonstrates preserved biologically relevant function with suitable controls, the available evidence cannot support BS3.
Still missing
  • A validated functional assay directly testing STK11 p.Arg304Gln/R304Q and demonstrating preserved function is needed.
  • Appropriate assay controls, biological relevance, and quantitative benign calibration for the exact variant are unavailable.
Sources
PMID:12552571 ↗PMID:17404884 ↗PMID:9837816 ↗
BS4 Not assessed: no tested unaffected relatives or phenotype-informed non-segregation observations are documented for c.911G>A (p.Arg304Gln). Details ▾Hide ▴
Reasoning

No informative unaffected relatives tested for NM_000455.5:c.911G>A (p.Arg304Gln) are documented, and no phenotype or age-dependent assessment is available to establish non-segregation. The absence of a reported family observation is not evidence that the variant fails to segregate with disease.

Rule
Generic ACMG/AMP BS4 requires the variant to be absent in affected family members or present in unaffected individuals when this is informative for the disease model; no such data are available.
Evidence considered
  • No tested unaffected relatives or phenotype-informed non-segregation data for NM_000455.5:c.911G>A (p.Arg304Gln) are documented.
  • The available literature does not provide a variant-specific non-segregation observation for c.911G>A.
Still missing
  • Genotypes of unaffected relatives
  • Reliable unaffected status and age-related penetrance assessment
  • Pedigree and phenotype data
  • Variant-positive and variant-negative relative comparison
BP1 BP1 could not be assessed because its agent did not produce valid output. Details ▾Hide ▴
Still missing
  • attempt 1: evidence_refs must contain only source_registry keys
  • attempt 2: evidence_refs must contain only source_registry keys
  • attempt 3: evidence_refs must contain only source_registry keys
BP2 Not assessed: no documented cis/trans phase or co-occurrence observation with a pathogenic STK11 variant is available. Details ▾Hide ▴
Reasoning

No applicable STK11-specific VCEP framework was available, so generic ACMG/AMP guidance was used. BP2 requires a documented co-occurrence and phase observation: the evaluated variant in cis with a pathogenic variant, or, for a dominant disorder, in trans with a pathogenic variant. The case evidence contains no affected-proband genotype, family segregation record, or laboratory phase result documenting either cis or trans co-occurrence with a pathogenic STK11 variant. The available ClinVar records and literature do not establish such an observation, so BP2 cannot be assessed.

Rule
BP2 requires documented cis or trans co-occurrence with a pathogenic variant; without phase-resolved co-occurrence data, BP2 is not assessed.
Evidence considered
  • Generic ACMG/AMP BP2 guidance requires documented cis or trans co-occurrence with a pathogenic variant.
  • ClinVar contains submissions for the exact variant but does not provide a phase-resolved co-occurrence observation with a pathogenic STK11 variant in the available case evidence.
  • The reviewed variant-specific literature does not report an affected-proband or family phase observation that could establish BP2.
Still missing
  • Affected-proband or family genotype data showing the evaluated variant and a pathogenic STK11 variant in cis or trans.
  • A validated laboratory or pedigree-based phase determination for any pathogenic co-occurring STK11 variant.
Sources
PMID:25741868 ↗clinvar ↗
BP5 Not assessed: no affected individual with a documented alternate molecular diagnosis is available to support BP5. Details ▾Hide ▴
Reasoning

No affected individual, phenotype, molecular diagnosis, or credible alternate genetic cause is documented for this case. The available ClinVar and literature records do not establish that this variant was found in a patient whose phenotype is explained by another pathogenic variant. Therefore BP5 cannot be assessed.

Rule
Generic ACMG/AMP BP5 requires the variant to be found in an affected individual with an alternative molecular basis for the phenotype; that case context is unavailable.
Evidence considered
  • The exact ClinVar record contains classification submissions but no clinical case description establishing an alternate molecular diagnosis.
  • The reviewed publications do not report this exact variant in an affected individual with a separate pathogenic explanation.
Still missing
  • Clinical case phenotype and molecular diagnostic context are unavailable.
  • No documented alternate pathogenic variant explaining an affected individual's phenotype is available.
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000455.5:c.911G>A in STK11 is a missense substitution predicted to produce NP_000446.1:p.(Arg304Gln). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_null_variant_class
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
PM3 N/ANot applicable: STK11-associated Peutz–Jeghers syndrome is autosomal dominant, so recessive biallelic evidence criterion PM3 does not apply. Details ▾Hide ▴
Reasoning

No applicable STK11-specific VCEP framework was available, so generic ACMG/AMP guidance was used. PM3 is intended for recessive disorders and requires the evaluated variant to be observed in trans with a pathogenic variant in affected individuals. STK11-associated Peutz–Jeghers syndrome is described as an autosomal-dominant disorder; therefore PM3 is not applicable to this variant. The available literature does not provide a phase-based affected-proband observation that would alter this inheritance-mode determination.

Rule
PM3 is not applicable because the associated STK11 disorder is autosomal dominant; PM3 is a recessive trans-phase criterion.
Evidence considered
  • The available STK11 clinical literature describes Peutz–Jeghers syndrome as an autosomal-dominant disorder.
  • Generic ACMG/AMP PM3 guidance concerns recessive inheritance and trans-phase observations; no STK11-specific VCEP specification was available.
  • No phase-resolved affected-proband observation was identified, but such an observation is not required to determine that PM3 is inapplicable for an autosomal-dominant disorder.
Sources
PMID:17404884 ↗PMID:25741868 ↗
PM4 N/APM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_000455.5:c.911G>A in STK11 is a missense substitution predicted to produce NP_000446.1:p.(Arg304Gln). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
BP3 N/ABP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_000455.5:c.911G>A in STK11 is a missense substitution predicted to produce NP_000446.1:p.(Arg304Gln). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_repeat_region_indel
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
pvs1_generic_framework ↗generic_acmg_combination_rules
BP7 N/ABP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000455.5:c.911G>A in STK11 is a missense substitution predicted to produce NP_000446.1:p.(Arg304Gln). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules

Identifiers

Gene
STK11
Transcript
NM_000455.5
Coding (HGVS c.)
NM_000455.5:c.911G>A
Protein (HGVS p.)
NP_000446.1:p.(Arg304Gln)
GRCh38
chr19:1221997 G>A
GRCh37
chr19:1221996 G>A
Location and type
Exon 7 · missense
ClinVar
419419
COSMIC
COSV109429977

Gene diagram

Every interpreted variant in STK11, mapped onto the exon structure of NM_000455.5. Select a row to find it on the plot.

STK11NM_000455.5
Fetching transcript structure from UCSC…
gnomAD v4.1 29 / 1,570,750 alleles AF 1.85e-05 · 0 homozygotes · FAF 2.58e-05
gnomAD v2.1 7 / 180,804 alleles AF 3.87e-05 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.8e-05 · 29 / 1,570,750 alleles · 0 hom · FAF 2.6e-05
Middle Eastern1 / 6,036 0.00017
African/African American5 / 73,778 6.8e-05
European (Finnish)2 / 59,624 3.4e-05
East Asian1 / 42,142 2.4e-05
Admixed American1 / 54,056 1.8e-05
European (non-Finnish)18 / 1,158,974 1.6e-05
South Asian1 / 85,536 1.2e-05
0 alternate alleles recorded in 3 other groups: Remaining individuals, Amish, Ashkenazi Jewish.

gnomAD v2.1

AF 3.9e-05 · 7 / 180,804 alleles · 0 hom
European (Finnish)3 / 16,334 0.00018
African/African American1 / 9,716 0.0001
South Asian1 / 24,246 4.1e-05
Admixed American1 / 27,684 3.6e-05
European (non-Finnish)1 / 76,160 1.3e-05
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, Remaining individuals.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.84625e-05; MAF= 0.00185%, 29/1570750 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165673; MAF= 0.01657%, 1/6036 alleles, homozygotes = 0); grpmax FAF= 2.579e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.8716e-05; MAF= 0.00387%, 7/180804 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000183666; MAF= 0.01837%, 3/16334 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -334 bp
0.002
SpliceAI acceptor gainat -71 bp
0.006
SpliceAI donor lossat +347 bp
0.000
SpliceAI donor gainat -151 bp
0.003
Pangolin splice lossmagnitude shown
-0.002
Pangolin splice gain
0.003

Other predictors

REVEL
0.567
BayesDel
-0.032

How the predictions were used

PP3 Not met: REVEL 0.567 is below the supporting PP3 threshold of 0.644 for missense variants. Details ▾Hide ▴
Reasoning

The variant is missense (NP_000446.1:p.(Arg304Gln)), so PP3 is evaluated using REVEL only; SpliceAI is not applicable to this missense protein-impact assessment. REVEL is 0.567, below the generic ClinGen SVI supporting PP3 threshold of >=0.644 from the supplied Pejaver et al. 2022 calibration (PMID:36413997), so PP3 is not met. BayesDel is not used because no generic ACMG-strength calibration is established.

Evidence considered
  • The normalized consequence is missense, p.(Arg304Gln), selecting the REVEL path and excluding SpliceAI for PP3/BP4.
  • REVEL score is 0.567; the supplied ClinGen SVI calibration assigns supporting PP3 at REVEL >=0.644 (Pejaver et al. 2022, PMID:36413997).
  • BayesDel is not used because the supplied rules state that no generic ACMG-strength calibration is established.
Sources
revel
BP4 Not met: REVEL 0.567 exceeds the supporting BP4 threshold of 0.29 for missense variants. Details ▾Hide ▴
Reasoning

The variant is missense (NP_000446.1:p.(Arg304Gln)), so BP4 is evaluated using REVEL only; the SpliceAI score cannot provide benign support for a missense variant. REVEL is 0.567, above the generic ClinGen SVI supporting BP4 threshold of <=0.29 from the supplied Pejaver et al. 2022 calibration (PMID:36413997), placing it in the non-benign-supporting gray zone; therefore BP4 is not met. BayesDel is not used because no generic ACMG-strength calibration is established.

Evidence considered
  • The normalized consequence is missense, p.(Arg304Gln), selecting the REVEL path and excluding SpliceAI for PP3/BP4.
  • REVEL score is 0.567; the supplied ClinGen SVI calibration assigns supporting BP4 at REVEL <=0.29 (Pejaver et al. 2022, PMID:36413997).
  • The REVEL result is intermediate rather than benign-supporting, and does not authorize substitution of the SpliceAI score.
  • BayesDel is not used because the supplied rules state that no generic ACMG-strength calibration is established.
Sources
revel
BP7 N/ABP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_000455.5:c.911G>A in STK11 is a missense substitution predicted to produce NP_000446.1:p.(Arg304Gln). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies. Details ▾Hide ▴
Rule
deterministic_prefilter: requires_synonymous
Evidence considered
  • Deterministic consequence classification: missense (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.567. BayesDel score = -0.0317247.

8 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

  • Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
    This paper presents general ACMG/AMP standards for interpreting sequence variants and provides the framework for using population-frequency evidence; it does not report variant-specific STK11 population data for c.911G>A (p.Arg304Gln).
    → PM2 · supporting Does not name this variant
    PMID 25741868 ↗
    Source detail
    The rules apply to all available data on a variant, whether gathered from the current case under investigation or from well-vetted previously published data.

    Location Proposed Criteria for Interpretation of Sequence Variants, page 7

    Context General consensus recommendations for sequence-variant interpretation; not a variant-specific cohort study.

Other recorded publications

  • Functional analysis of LKB1/STK11 mutants and two aberrant isoforms found in Peutz-Jeghers Syndrome patients.
    Boudeau J et al. · 2003
    The paper studied the different same-residue substitution R304W and five other STK11 variants identified in Peutz-Jeghers syndrome. The variants, including R304W, lacked detectable autophosphorylation and p53 phosphorylation in vitro, R304W was exclusively nuclear, and the variants failed to suppress growth of G361 melanoma cells; the paper did not test R304Q.
    Does not name this variant
    PMID 12552571 ↗
    Quoted passage
    Interestingly, none of the six PJS LKB1 variants investigated possessed the ability to autophosphorylate or phosphorylate the p53 protein, despite similar amounts of these proteins being added to the kinase assays as wild type LKB1 (Fig. 1B, D).

    Results, sections "Kinase activity of PJS LKB1 variants," "Subcellular localisation of LKB1," and "Ability to suppress cell growth"

  • Loss of LKB1 kinase activity in Peutz-Jeghers syndrome, and evidence for allelic and locus heterogeneity.
    The paper reports functional testing of STK11 variants D176N, W308C, L67P, and K78I in COS7 cells; all four showed no or very little autophosphorylation compared with wild-type LKB1. It did not test R304Q.
    Does not name this variant
    PMID 9837816 ↗
    Quoted passage
    As shown in figure 3, although equal amounts of each protein were assayed (as shown by the anti-myc staining of the hybrid proteins), no or very little autophosphorylation was observed in all four mutant LKB1s compared with normal samples, which clearly shows the loss of kinase activity of LKB1.

    Results and Discussion, "Loss of Protein Kinase Activity of Mutant LKB1 in PJS Patients," p. 1648

  • Molecular and clinical characteristics in 46 families affected with Peutz-Jeghers syndrome.
    Mehenni H et al. · 2007
    The paper reports other STK11 missense variants, including c.910C>T (R304W), and describes autophosphorylation assays in which mutant LKB1/STK11 proteins lacked autophosphorylation while wild-type protein was autophosphorylated. It did not test R304Q.
    Does not name this variant
    PMID 17404884 ↗
    Quoted passage
    Missense mutations have occurred within the kinase domain in highly conserved residues of diverse species (human, mouse, xenopus). When assayed by autophosphorylation, the protein kinase activities of the normal and mutant LKB1/STK11s show a complete absence of autophosphorylation, leading to inactivation of the protein kinase of the mutants but not the LKB1/STK11 wild type [9, 21] (Fig. 1).

    Results, "LKB1/STK11 germline mutations" subsection; Table 1 lists c.910C>T (R304W) in families GE31 and GE34; Fig. 1

  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    No paper-specific finding is recorded.
    PMID 26467025 ↗
  • ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
    Green RC et al. · 2013
    This ACMG policy paper does not mention STK11 or c.911G>A/p.Arg304Gln and provides no variant-specific clinical, phenotype, prevalence, or expert-panel classification evidence.
    Does not name this variant
    PMID 23788249 ↗
  • ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
    This ACMG policy paper does not discuss STK11 or c.911G>A/p.Arg304Gln and provides no variant-specific clinical, phenotype, prevalence, or expert-panel classification evidence.
    Does not name this variant
    PMID 25356965 ↗
  • Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
    No paper-specific finding is recorded.
    PMID 28492532 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 29 / 1,570,750 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.006 Open source ↗
ClinVar 10 Uncertain significance · 1 Likely benign · 1 Uncertain Significance Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 1.84625e-05; MAF= 0.00185%, 29/1570750 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000165673; MAF= 0.01657%, 1/6036 alleles, homozygotes = 0); grpmax FAF= 2.579e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.8716e-05; MAF= 0.00387%, 7/180804 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 0.000183666; MAF= 0.01837%, 3/16334 alleles, homozygotes = 0).

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (10 clinical laboratories) and as Likely benign (1 clinical laboratory) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 419419)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.567. BayesDel score = -0.0317247.

Functional

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. STK11, a tumor suppressor and intracellular kinase, is frequently mutated in lung cancer.

Somatic

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV109429977, n = 1 times).

Cancer Hotspots

This variant lies in a statistically significant hotspot.