About STK11
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
STK11 c.49C>G, p.(Leu17Val)
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
PM2Moderate
PM2 · moderate
Population frequency is below the 0.1% rarity threshold used for this non-VCEP review: gnomAD v2.1 AF is 0.00074% (2/269894), gnomAD v4.1 AF is 0.00019% (3/1609476), the highest observed subpopulation frequency is 0.00875% in gnomAD v2.1 African/African American samples, and the variant is absent from gnomAD-Canada.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple computational results support a benign effect. SpliceAI predicts no significant splice impact with a max delta score of 0.01, below a 0.2 splice-concern threshold; REVEL is 0.15, consistent with a low missense deleteriousness prediction; and BayesDel is negative at -0.30256, arguing against a damaging 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 moderate, BP4 supporting; combination = 1 moderate + 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
3 / 1,609,476 alleles
gnomAD v4.1: 3 / 1,609,476 alleles. Recorded AF 1.86396e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.41032e-06; MAF= 0.00074%, 2/269894 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.75044e-05; MAF= 0.00875%, 2/22856 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
7 reported laboratory submissions
6 Uncertain significance · 1 Uncertain Significance.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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 · 5 not met · 13 not assessed · 8 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.49C>G (p.Leu17Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar only as a variant of uncertain significance by single submitters.
This variant is rare in population databases, with gnomAD v2.1 AF 0.00074% (2/269894), gnomAD v4.1 AF 0.00019% (3/1609476), a highest observed subpopulation frequency of 0.00875% in gnomAD v2.1 African/African American samples, and no observation in gnomAD-Canada.
Computational evidence supports a benign effect, with SpliceAI max delta 0.01 indicating no significant splice impact, REVEL 0.15 indicating a low deleteriousness prediction, and BayesDel -0.30256 arguing against a damaging missense effect.
No criteria match.
Met · 2
PM2 ModeratePopulation frequency is below the 0.1% rarity threshold used for this non-VCEP review: gnomAD v2.1 AF is 0.00074% (2/269894), gnomAD v4.1 AF is 0.00019% (3/1609476), the highest observed subpopulation frequency is 0.00875% in gnomAD v2.1 African/African American samples, and the variant is absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 total AF 7.41032e-06
- highest subpopulation AF 8.75044e-05.
- gnomAD v4.1 total AF 1.86396e-06
- highest subpopulation AF 2.67294e-05
- grpmax FAF 4.44e-06.
- Absent from gnomAD-Canada v1.0.
Sources
BP4 SupportingMultiple computational results support a benign effect. SpliceAI predicts no significant splice impact with a max delta score of 0.01, below a 0.2 splice-concern threshold; REVEL is 0.15, consistent with a low missense deleteriousness prediction; and BayesDel is negative at -0.30256, arguing against a damaging effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL score 0.15.
- BayesDel score -0.30256.
Sources
Not met · 5 · evaluated, threshold not reached
PS4 This variant has been reported in ClinVar only as a variant of uncertain significance by single submitters, and no case-control or statistically increased prevalence data were identified. Details ▾Hide ▴
Evidence considered
- ClinVar shows 7 single-submitter VUS classifications and no expert panel review.
Still missing
- No case-control enrichment data were identified.
- No well-documented series of affected probands attributable to this variant were identified.
Sources
PM1 This variant does not lie in a statistically significant hotspot, and no evidence was identified that codon 17 is a well-established critical functional residue without benign variation. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots did not identify this variant in a statistically significant hotspot.
Still missing
- No critical-region evidence specific to residue 17 was identified.
Sources
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below a 0.2 splice-concern threshold, REVEL is 0.15, and BayesDel is -0.30256; together these findings do not support PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL score 0.15.
- BayesDel score -0.30256.
Sources
BA1 Population frequency does not meet the stand-alone benign threshold of greater than 1%. The highest observed frequency is 0.00875% in gnomAD v2.1 African/African American samples, well below 1%. Details ▾Hide ▴
Evidence considered
- Highest observed subpopulation AF in gnomAD v2.1 is 8.75044e-05.
- Highest observed subpopulation AF in gnomAD v4.1 is 2.67294e-05.
Sources
BS1 Population frequency does not exceed the benign strong threshold of greater than 0.3%. The highest observed frequency is 0.00875% in gnomAD v2.1 African/African American samples, which is below 0.3%. Details ▾Hide ▴
Evidence considered
- Highest observed subpopulation AF in gnomAD v2.1 is 8.75044e-05.
- Highest observed subpopulation AF in gnomAD v4.1 is 2.67294e-05.
Sources
Not assessed · 13 · no assessment recorded
PS1 No established pathogenic variant causing the same amino acid change was identified, so PS1 was not assessed. Details ▾Hide ▴
Still missing
- No verified pathogenic comparator with the same amino acid substitution was identified.
PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant. Details ▾Hide ▴
Still missing
- No de novo case data were identified.
PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence for STK11 p.(Leu17Val).
Still missing
- No variant-specific validated functional assay data were identified.
Sources
PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant. Details ▾Hide ▴
Still missing
- No de novo case data were identified.
PP1 No segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- No family segregation studies were identified.
PP2 Available evidence was insufficient to determine whether STK11 missense variants are sufficiently enriched among pathogenic variants at this gene to support PP2 for this variant. Details ▾Hide ▴
Still missing
- No gene-level missense constraint or pathogenic missense enrichment evidence was identified for PP2.
PP4 No phenotype or family history evidence was identified showing a highly specific clinical presentation attributable to this variant. Details ▾Hide ▴
Still missing
- No case-specific phenotype data were identified.
BS2 No evidence was identified showing this variant in healthy adult individuals in a manner sufficient for BS2. Details ▾Hide ▴
Evidence considered
- No homozygotes were observed in gnomAD v2.1 or v4.1.
Still missing
- No phenotype-confirmed healthy carrier data were identified.
Sources
BS3 No well-established functional studies demonstrating normal protein function for this specific variant were identified. Details ▾Hide ▴
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence for STK11 p.(Leu17Val).
Still missing
- No variant-specific validated functional assay data were identified.
Sources
BS4 No lack-of-segregation data were identified for this variant. Details ▾Hide ▴
Still missing
- No family segregation studies were identified.
BP1 Available evidence was insufficient to conclude that a missense change in STK11 should be down-weighted under BP1 for this variant. Details ▾Hide ▴
Still missing
- No gene-level evidence set was identified to justify BP1 use for STK11 missense variation.
BP2 No phase data with another pathogenic variant were identified for this variant. Details ▾Hide ▴
Still missing
- No cis/trans phase data were identified.
BP5 No alternate molecular explanation for the relevant phenotype was identified. Details ▾Hide ▴
Still missing
- No case-specific phenotype and alternative-cause data were identified.
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and the generic PVS1 framework does not apply because it is not a nonsense, frameshift, or canonical +/-1,2 splice variant even though STK11 loss of function is an established disease mechanism. Details ▾Hide ▴
Evidence considered
- STK11 loss of function is supported as a germline disease mechanism.
- NM_000455.5:c.49C>G is a missense change p.(Leu17Val) outside the default generic PVS1 null-variant categories.
Sources
PM3 N/APM3 is not applicable because no recessive disease context or trans configuration evidence was identified for this STK11 variant. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 is not applicable because this variant is a missense substitution and does not cause a protein length change or in-frame exon-level alteration. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 was not applied because classic same-residue PM5 eligibility could not be confirmed safely and no validated pathogenic same-residue comparator variants were identified. Details ▾Hide ▴
Evidence considered
- PM5 candidate review flagged classic same-residue PM5 semantics as unconfirmed and found no comparator candidates.
Still missing
- No verified same-residue pathogenic comparator was identified under a confirmed PM5 rule.
Sources
pm5_candidates
PP5 N/APP5 was not used. ClinVar contains only single-submitter uncertain significance assertions without validated primary evidence that would support pathogenic classification. Details ▾Hide ▴
Evidence considered
- ClinVar has no expert panel submission and no usable criterion-lead submissions for this variant.
Sources
BP3 N/ABP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP6 N/ABP6 was not used. No reputable source benign or likely benign assertion with sufficient supporting evidence was identified; ClinVar shows only uncertain significance submissions. Details ▾Hide ▴
Evidence considered
- ClinVar reports only VUS submissions and no expert panel benign assertion.
Sources
BP7 N/ABP7 is not applicable because this is a missense variant, not a synonymous or deep intronic change. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- STK11
- Transcript
- NM_000455.5
- Coding (HGVS c.)
- NM_000455.5:c.49C>G
- Protein (HGVS p.)
- NP_000446.1:p.(Leu17Val)
- GRCh38
- chr19:1206962 C>G
- GRCh37
- chr19:1206961 C>G
- ClinVar
- 458049
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
3 / 1,609,476 alleles
AF 1.86e-06 · 0 homozygotes · FAF 4.44e-06
gnomAD v2.1
2 / 269,894 alleles
AF 7.41e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,609,476 alleles · 0 hom · FAF 4.4e-06
| African/African American2 / 74,824 | 2.7e-05 |
| European (non-Finnish)1 / 1,178,234 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 7.4e-06 · 2 / 269,894 alleles · 0 hom
| African/African American2 / 22,856 | 8.8e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.86396e-06; MAF= 0.00019%, 3/1609476 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.67294e-05; MAF= 0.00267%, 2/74824 alleles, homozygotes = 0); grpmax FAF= 4.44e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.41032e-06; MAF= 0.00074%, 2/269894 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.75044e-05; MAF= 0.00875%, 2/22856 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.150
- BayesDel
- -0.303
How the predictions were used
BP4 SupportingMultiple computational results support a benign effect. SpliceAI predicts no significant splice impact with a max delta score of 0.01, below a 0.2 splice-concern threshold; REVEL is 0.15, consistent with a low missense deleteriousness prediction; and BayesDel is negative at -0.30256, arguing against a damaging effect. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL score 0.15.
- BayesDel score -0.30256.
Sources
PP3 Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below a 0.2 splice-concern threshold, REVEL is 0.15, and BayesDel is -0.30256; together these findings do not support PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score 0.01.
- REVEL score 0.15.
- BayesDel score -0.30256.
Sources
BP7 N/ABP7 is not applicable because this is a missense variant, not a synonymous or deep intronic change. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.15. BayesDel score = -0.30256.
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
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PMID 25645574 ↗ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.Syngal S et al. · 2015No paper-specific finding is recorded.
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PMID 25741868 ↗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.No paper-specific finding is recorded.
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PMID 31672839 ↗Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium.No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
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PMID 20301443 ↗Peutz-Jeghers Syndrome.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 23788249 ↗ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.Green RC et al. · 2013No paper-specific finding is recorded.
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PMID 25356965 ↗ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.ACMG Board of Directors · 2015No paper-specific finding is recorded.
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,609,476 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
6 Uncertain significance · 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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/458049/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/19-1206961-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr19-1206962-C-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/19-1206962-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000455.5%3Ac.49C%…
- OncoKB ↗www.oncokb.org/gene/STK11/L17V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=STK11+c.49C%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= 1.86396e-06; MAF= 0.00019%, 3/1609476 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.67294e-05; MAF= 0.00267%, 2/74824 alleles, homozygotes = 0); grpmax FAF= 4.44e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.41032e-06; MAF= 0.00074%, 2/269894 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.75044e-05; MAF= 0.00875%, 2/22856 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 458049)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.15. BayesDel score = -0.30256.
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 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.