About STK11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
STK11 c.22C>G, p.(Gln8Glu)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is very rare in population databases, with AF 4.6322e-06 in gnomAD v2.1 and AF 2.50785e-06 in gnomAD v4.1, both below the 0.1% PM2 threshold used for non-VCEP review.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple computational results support no significant impact: SpliceAI predicts no significant splice effect with max delta score 0.00, REVEL is 0.032, and BayesDel is -0.435498, together arguing against a deleterious effect.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS because the evidence is conflicting.
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
4 / 1,594,994 alleles
gnomAD v4.1: 4 / 1,594,994 alleles. Recorded AF 2.50785e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.6322e-06; MAF= 0.00046%, 1/215880 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.03814e-05; MAF= 0.00104%, 1/96326 alleles, homozygotes = 0).
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: STK11, a tumor suppressor and intracellular kinase, is frequently mutated in lung cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 6 not met · 15 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The STK11 c.22C>G (p.Gln8Glu) variant has been reported in ClinVar as uncertain significance by five clinical laboratory submissions.
This variant is very rare in population databases, with AF 4.6322e-06 in gnomAD v2.1 and AF 2.50785e-06 in gnomAD v4.1, supporting rarity but not a benign frequency threshold.
Computational evidence supports no significant impact on splicing or protein function, with SpliceAI max delta score 0.00, REVEL 0.032, and BayesDel -0.435498.
No criteria match.
Met · 2
PM2 SupportingThis variant is very rare in population databases, with AF 4.6322e-06 in gnomAD v2.1 and AF 2.50785e-06 in gnomAD v4.1, both below the 0.1% PM2 threshold used for non-VCEP review. Details ▾Hide ▴
Rule
Absent from controls or at extremely low frequency if consistent with disease prevalence and penetrance.
Evidence considered
- gnomAD v2.1: 1/215880 alleles
- AF 4.632203075782842e-06
- 0 homozygotes
- gnomAD v4.1: 4/1594994 alleles
- AF 2.5078464245006564e-06
Sources
BP4 SupportingMultiple computational results support no significant impact: SpliceAI predicts no significant splice effect with max delta score 0.00, REVEL is 0.032, and BayesDel is -0.435498, together arguing against a deleterious effect. Details ▾Hide ▴
Rule
Multiple computational lines of evidence suggest no impact on gene or gene product.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL score 0.032
- BayesDel score -0.435498
Sources
Not met · 6 · evaluated, threshold not reached
PM1 Available evidence does not place p.(Gln8Glu) in a statistically significant hotspot, and no critical STK11 functional region at residue 8 was identified from the reviewed sources. Details ▾Hide ▴
Rule
Located in a mutational hotspot and/or critical and well-established functional domain without benign variation.
Evidence considered
- Cancer Hotspots review found no hotspot row for STK11 residue Q8
Still missing
- No curated domain-specific source for residue 8 was available among the retrieved materials.
Sources
PP3 Available computational evidence does not support a deleterious effect: SpliceAI predicts no significant splice impact with max delta score 0.00, REVEL is low at 0.032, and BayesDel is negative at -0.435498. Details ▾Hide ▴
Rule
Multiple computational lines of evidence support a deleterious effect.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL score 0.032
- BayesDel score -0.435498
Sources
PP5 ClinVar reports this variant as uncertain significance rather than as a pathogenic or likely pathogenic variant from a reputable source. Details ▾Hide ▴
Rule
Reputable source recently reports variant as pathogenic, but the evidence is not available for independent evaluation.
Evidence considered
- ClinVar overall classification: Uncertain significance
Sources
BA1 Population frequency does not reach the standalone benign threshold: AF is 4.6322e-06 in gnomAD v2.1 and 2.50785e-06 in gnomAD v4.1, both far below 1%. Details ▾Hide ▴
Rule
Allele frequency is above the disease-specific or generic standalone benign threshold.
Evidence considered
- gnomAD v2.1 AF 4.632203075782842e-06
- gnomAD v4.1 AF 2.5078464245006564e-06
Sources
BS1 Population frequency does not exceed the strong benign threshold: AF is 4.6322e-06 in gnomAD v2.1 and 2.50785e-06 in gnomAD v4.1, both far below 0.3%. Details ▾Hide ▴
Rule
Allele frequency is greater than expected for the disorder.
Evidence considered
- gnomAD v2.1 AF 4.632203075782842e-06
- gnomAD v4.1 AF 2.5078464245006564e-06
Sources
BP6 ClinVar does not report this variant as benign or likely benign from a reputable source; the available submissions classify it as uncertain significance. Details ▾Hide ▴
Rule
Reputable source recently reports variant as benign, but the evidence is not available for independent evaluation.
Evidence considered
- ClinVar overall classification: Uncertain significance
Sources
Not assessed · 15 · no assessment recorded
PS1 No evidence was identified showing that this amino acid change has already been established as pathogenic from a different nucleotide change. Details ▾Hide ▴
Rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
Evidence considered
- ClinVar record reviewed for the queried variant only
Still missing
- No curated same-amino-acid pathogenic comparator was available.
Sources
PS2 No confirmed de novo occurrence with parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
De novo occurrence in a patient with the disease and no family history, with maternity and paternity confirmed.
Still missing
- No case-level parental testing data were available.
PS3 No validated functional study demonstrating a damaging effect of this specific STK11 variant was identified. Details ▾Hide ▴
Rule
Well-established functional studies supportive of a damaging effect.
Still missing
- No exact-variant functional assay was available.
PS4 This variant is present in ClinVar, but no proband count, case-control enrichment, or other case-level data sufficient to show increased prevalence in affected individuals was identified. Details ▾Hide ▴
Rule
Prevalence in affected individuals is significantly increased compared with controls.
Evidence considered
- ClinVar lists uncertain significance submissions only
Still missing
- No qualifying case-control data were available.
- No exact-variant affected-proband tally was available.
Sources
PM5 No established pathogenic missense comparator at codon 8 was identified from the reviewed evidence. Details ▾Hide ▴
Rule
Novel missense change at an amino acid residue where a different pathogenic missense change has been seen before.
Evidence considered
- ClinVar record reviewed for the queried variant only
Still missing
- No curated same-codon pathogenic comparator assessment was available.
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Rule
Assumed de novo occurrence without confirmation of maternity and paternity.
Still missing
- No family-based case report was available.
PP1 No segregation data were identified for this variant in affected family members. Details ▾Hide ▴
Rule
Cosegregation with disease in multiple affected family members in a gene definitively known to cause the disease.
Still missing
- No pedigree or cosegregation data were available.
PP2 The reviewed evidence did not provide a gene-specific basis to apply PP2 for this missense variant. Details ▾Hide ▴
Rule
Missense variant in a gene with low rate of benign missense variation and where missense variants are a common mechanism of disease.
Still missing
- No retrieved source quantified a low benign missense rate with missense variants as a common disease mechanism for this rule.
PP4 No patient-specific phenotype information was available to determine whether the clinical presentation is highly specific for STK11-related disease. Details ▾Hide ▴
Rule
Patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
Evidence considered
- STK11 disease-context sources reviewed
- but no individual phenotype data were available
Still missing
- No phenotype summary or diagnostic features for an individual carrier were provided.
Sources
BS2 No evidence was identified showing this variant in well-phenotyped healthy adult individuals in a way that would strongly argue against pathogenicity. Details ▾Hide ▴
Rule
Observed in healthy adult individuals for a fully penetrant dominant disorder at an age consistent with full penetrance.
Evidence considered
- gnomAD shows rare alleles but no phenotyped healthy-carrier evidence
Still missing
- No healthy-carrier dataset beyond aggregate population counts was available.
Sources
BS3 No validated functional study demonstrating normal STK11 function for this specific variant was identified. Details ▾Hide ▴
Rule
Well-established functional studies show no damaging effect on protein function or splicing.
Still missing
- No exact-variant benign functional assay was available.
BS4 No non-segregation data were identified for this variant. Details ▾Hide ▴
Rule
Lack of segregation in affected members of a family.
Still missing
- No family study documenting lack of segregation was available.
BP1 The reviewed evidence did not provide a sufficient gene-specific basis to apply BP1 to this missense variant. Details ▾Hide ▴
Rule
Missense variant in a gene for which primarily truncating variants are known to cause disease.
Still missing
- No retrieved source established that truncating variants predominate strongly enough over pathogenic missense variants for BP1.
BP2 No phase data or second-variant data were identified to support BP2. Details ▾Hide ▴
Rule
Observed in trans with a pathogenic variant for a dominant disorder, or in cis with a pathogenic variant in any inheritance pattern.
Still missing
- No trans/cis observations with another variant were available.
BP5 No alternate molecular explanation for an affected individual's phenotype was identified. Details ▾Hide ▴
Rule
Variant found in a case with an alternate molecular basis for disease.
Still missing
- No case-level genotype and phenotype context was available.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ASTK11 loss of function is an established disease mechanism, but NM_000455.5:c.22C>G is a missense variant p.(Gln8Glu)/p.(Q8E) and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants. Details ▾Hide ▴
Rule
Apply generic PVS1 only to qualifying loss-of-function variant classes after gene-level loss-of-function eligibility is established.
Evidence considered
- STK11 loss-of-function mechanism supported at the gene level
- Variant consequence is missense p.(Gln8Glu)/p.(Q8E)
- Generic PVS1 scaffold states this variant is outside default PVS1 null-variant buckets
Sources
PM3 N/APM3 is not applicable because STK11-related Peutz-Jeghers syndrome is not assessed here as a recessive disorder requiring trans observations. Details ▾Hide ▴
Rule
For recessive disorders, detected in trans with a pathogenic variant.
Evidence considered
- Reviewed STK11 disease-context sources for hereditary syndrome background
Sources
PM4 N/APM4 is not applicable because this variant is a missense substitution and does not change protein length through an in-frame insertion, deletion, or stop-loss event. Details ▾Hide ▴
Rule
Protein length changes due to in-frame deletions/insertions or stop-loss variants.
Evidence considered
- Variant consequence is missense p.(Gln8Glu)/p.(Q8E)
Sources
pvs1_variant_assessment
BP3 N/ABP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
Rule
In-frame deletions/insertions in a repetitive region without a known function.
Evidence considered
- Variant consequence is missense p.(Gln8Glu)/p.(Q8E)
Sources
pvs1_variant_assessment
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous or deep intronic change. Details ▾Hide ▴
Rule
Synonymous or noncoding variant with no predicted splice impact and no nucleotide conservation evidence supporting pathogenicity.
Evidence considered
- Variant consequence is missense p.(Gln8Glu)/p.(Q8E)
Sources
Identifiers
- Gene
- STK11
- Transcript
- NM_000455.5
- Coding (HGVS c.)
- NM_000455.5:c.22C>G
- Protein (HGVS p.)
- NP_000446.1:p.(Gln8Glu)
- GRCh38
- chr19:1206935 C>G
- GRCh37
- chr19:1206934 C>G
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in STK11
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
4 / 1,594,994 alleles
AF 2.51e-06 · 0 homozygotes · FAF 8e-07
gnomAD v2.1
1 / 215,880 alleles
AF 4.63e-06 · 0 homozygotes
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,594,994 alleles · 0 hom · FAF 8e-07
| European (non-Finnish)4 / 1,171,290 | 3.4e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4.6e-06 · 1 / 215,880 alleles · 0 hom
| European (non-Finnish)1 / 96,326 | 1e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.50785e-06; MAF= 0.00025%, 4/1594994 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.41504e-06; MAF= 0.00034%, 4/1171290 alleles, homozygotes = 0); grpmax FAF= 8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.6322e-06; MAF= 0.00046%, 1/215880 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.03814e-05; MAF= 0.00104%, 1/96326 alleles, homozygotes = 0).
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingMultiple computational results support no significant impact: SpliceAI predicts no significant splice effect with max delta score 0.00, REVEL is 0.032, and BayesDel is -0.435498, together arguing against a deleterious effect. Details ▾Hide ▴
Rule
Multiple computational lines of evidence suggest no impact on gene or gene product.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL score 0.032
- BayesDel score -0.435498
Sources
PP3 Available computational evidence does not support a deleterious effect: SpliceAI predicts no significant splice impact with max delta score 0.00, REVEL is low at 0.032, and BayesDel is negative at -0.435498. Details ▾Hide ▴
Rule
Multiple computational lines of evidence support a deleterious effect.
Evidence considered
- SpliceAI max delta score 0.00
- REVEL score 0.032
- BayesDel score -0.435498
Sources
BP7 N/ABP7 is not applicable because this is a missense variant rather than a synonymous or deep intronic change. Details ▾Hide ▴
Rule
Synonymous or noncoding variant with no predicted splice impact and no nucleotide conservation evidence supporting pathogenicity.
Evidence considered
- Variant consequence is missense p.(Gln8Glu)/p.(Q8E)
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.032. BayesDel score = -0.435498.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
4 / 1,594,994 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
Open source ↗
ClinVar
Captured ClinVar source record
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/527816/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-1206934-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-1206935-C-G?dataset=gnomad_r4
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000455.5%3Ac.22C%…
- OncoKB ↗www.oncokb.org/gene/STK11/Q8E
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=STK11+c.22C%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
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= 2.50785e-06; MAF= 0.00025%, 4/1594994 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.41504e-06; MAF= 0.00034%, 4/1171290 alleles, homozygotes = 0); grpmax FAF= 8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.6322e-06; MAF= 0.00046%, 1/215880 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.03814e-05; MAF= 0.00104%, 1/96326 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Uncertain Significance (1 clinical laboratory).
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.032. BayesDel score = -0.435498.
Functional
OncoKB has not reviewed this specific variant; no variant-level oncogenicity or biological effect is available. Gene-level context: STK11, a tumor suppressor and intracellular kinase, is frequently mutated in lung cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.