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STK11c.112C>GUncertain significance
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Variant interpretation report

STK11 c.112C>G, p.(Pro38Ala)

NM_000455.5:c.112C>G NP_000446.1:p.(Pro38Ala) 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

No gene-level summary was recorded for this case.

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

NM_000455.5:c.112C>G is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF = 5.58e-06; 9/1,613,804 alleles, no homozygotes). This is well below the 0.1% threshold for PM2 in the generic ACMG/AMP framework. The variant is also absent from gnomAD-Canada v1.0.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splice impact (max delta = 0.0). REVEL score is 0.328, below pathogenic thresholds. BayesDel score is -0.085 (negative, favoring a benign interpretation). These findings meet BP4 at supporting benign level.

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 benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.

02The sources

Evidence at a glance

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

SpliceAI score
0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
8 reported laboratory submissions

7 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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

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

29 criteria with recorded statuses: 2 met · 6 not met · 16 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000455.5:c.112C>G (p.Pro38Ala) in STK11 is a missense variant with no functional, segregation, or case-control data available.

The variant is extremely rare in population databases, absent from gnomAD v2.1 and present in gnomAD v4.1 at AF=5.58e-06 (9/1,613,804 alleles), meeting PM2 at supporting level.

Multiple in silico tools predict no deleterious effect: SpliceAI max delta=0.0, REVEL=0.328, BayesDel=-0.085, meeting BP4 at supporting benign level.

ClinVar reports the variant as Uncertain Significance by multiple clinical laboratories (Variation ID 458014) with no expert panel classification.

The variant does not reside in a known functional domain or mutational hotspot. No same-residue pathogenic comparator (PM5) or de novo evidence (PS2/PM6) was identified.

Overall, the available evidence is limited to population frequency data (PM2_supporting) and computational predictions (BP4_supporting_benign), which offset each other. The variant remains a Variant of Uncertain Significance.

Met · 2

PM2 SupportingNM_000455.5:c.112C>G is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF = 5.58e-06; 9/1,613,804 alleles, no homozygotes). This is well below the 0.1% threshold for PM2 in the generic ACMG/AMP framework. The variant is also absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1
  • gnomAD v4.1 AF=5.58e-06 (9/1
  • 613
  • 804)
  • absent from gnomAD-Canada.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splice impact (max delta = 0.0). REVEL score is 0.328, below pathogenic thresholds. BayesDel score is -0.085 (negative, favoring a benign interpretation). These findings meet BP4 at supporting benign level. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.0
  • REVEL=0.328
  • BayesDel=-0.085 (favoring benign).
Sources
spliceai ↗revelbayesdel

Not met · 6 · evaluated, threshold not reached

PS4 No case-control studies or cohort analyses demonstrate enrichment of NM_000455.5:c.112C>G in affected individuals. The variant is observed in 9/1,613,804 alleles in gnomAD v4.1 (AF = 5.58e-06). No published studies document the variant in multiple unrelated affected individuals. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1: 9/1
  • 613
  • 804 alleles (AF=5.58e-06)
  • no case-control enrichment data.
Still missing
  • No case-control or cohort enrichment data for this variant.
Sources
gnomad_v4 ↗clinvar ↗3167283933471991
PP3 Multiple in silico tools do not support a deleterious effect for NM_000455.5:c.112C>G (p.Pro38Ala). SpliceAI predicts no splice impact (max delta = 0.0). REVEL score is 0.328, below commonly used pathogenic thresholds (>0.5). BayesDel score is -0.085 (negative, favoring a benign interpretation). Multiple lines of computational evidence do not support pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.0
  • REVEL=0.328
  • BayesDel=-0.085.
Sources
spliceai ↗revelbayesdel
BA1 The allele frequency of NM_000455.5:c.112C>G in gnomAD v4.1 is 5.58e-06 (0.00056%), far below the 1% BA1 threshold. This does not support classification as benign based on population frequency. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=5.58e-06
  • well below the 1% BA1 threshold.
Sources
gnomad_v4 ↗
BS1 The allele frequency of NM_000455.5:c.112C>G in gnomAD v4.1 is 5.58e-06 (0.00056%), well below the 0.3% BS1 threshold. This does not support classification as benign based on population frequency. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF=5.58e-06
  • well below the 0.3% BS1 threshold.
Sources
gnomad_v4 ↗
BP1 BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. While STK11 has pathogenic truncating variants, it also has well-established pathogenic missense variants, particularly in the kinase domain. A missense change in STK11 does not automatically qualify for BP1. Details ▾Hide ▴
Evidence considered
  • STK11 has both truncating and missense pathogenic variants
  • BP1 criteria not met.
BP7 BP7 applies to synonymous variants with no predicted splice impact. NM_000455.5:c.112C>G is a missense variant (p.Pro38Ala), resulting in a non-conservative amino acid substitution from proline to alanine. BP7 does not apply to missense variants. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 criteria require a synonymous variant.

Not assessed · 16 · no assessment recorded

PS1 No evidence of a different pathogenic missense change at the same amino acid residue (Pro38) was identified. No comparator variant with a different amino acid substitution at Pro38 classified as pathogenic was found in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator identified.
Still missing
  • No pathogenic comparator at Pro38 available.
PS2 No de novo reports were identified for NM_000455.5:c.112C>G in the available literature or ClinVar submissions. Details ▾Hide ▴
Evidence considered
  • No de novo evidence identified.
Still missing
  • No de novo confirmation data available.
PS3 No well-established functional studies demonstrating a damaging effect for NM_000455.5:c.112C>G (p.Pro38Ala) were identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional evidence. No publications with functional characterization of this variant were found. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional studies identified.
Still missing
  • No functional data available for this variant.
Sources
oncokb ↗
PM1 The variant resides at codon 38 (p.Pro38Ala), which is in the N-terminal region of STK11, upstream of the kinase domain (residues ~49-309). The Cancer Hotspots database indicates this residue is not in a statistically significant somatic hotspot. Without a VCEP-defined critical functional domain map for STK11, PM1 cannot be reliably applied in the generic ACMG framework. Details ▾Hide ▴
Evidence considered
  • Residue Pro38 not in a statistically significant hotspot
  • N-terminal region upstream of kinase domain.
Still missing
  • No VCEP-defined critical domain map for STK11.
PM5 No confirmed pathogenic missense variant at the same amino acid residue (Pro38) with a different amino acid substitution was identified. The automated PM5 candidate search returned no candidates. Details ▾Hide ▴
Evidence considered
  • No same-residue pathogenic comparator variant identified at Pro38.
Still missing
  • No pathogenic comparator at Pro38 available.
Sources
pm5_candidates
PM6 No de novo reports were identified for NM_000455.5:c.112C>G. PM6 requires confirmed de novo occurrence with both parental relationships confirmed. Details ▾Hide ▴
Evidence considered
  • No de novo evidence available.
Still missing
  • No de novo confirmation data.
PP1 No segregation data are available for NM_000455.5:c.112C>G. No family studies documenting co-segregation with disease were identified in the literature. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family segregation studies available.
PP4 No specific phenotypic data are available for individuals carrying NM_000455.5:c.112C>G. While STK11 is associated with Peutz-Jeghers syndrome, the variant's extremely low population frequency precludes phenotype-genotype correlation without individual-level clinical data. Details ▾Hide ▴
Evidence considered
  • No individual-level phenotype data for variant carriers.
Still missing
  • No clinical phenotype data for variant carriers.
PP5 No reputable source has classified NM_000455.5:c.112C>G as pathogenic. All ClinVar submissions from clinical laboratories classify this variant as Uncertain Significance. The ClinVar-cited literature (PMID:33471991) is a breast cancer association study without confirmed variant-level evidence for this specific variant. Details ▾Hide ▴
Evidence considered
  • ClinVar consensus: VUS
  • no reputable pathogenic classification.
Still missing
  • No authoritative pathogenic classification.
Sources
clinvar ↗33471991
BS2 While 9 alleles are observed in gnomAD v4.1 (no homozygotes), the number is too low to assess whether the variant is observed in healthy adults at a frequency expected for a fully penetrant disorder. Individual phenotype data for gnomAD carriers are not available. Details ▾Hide ▴
Evidence considered
  • 9 alleles in gnomAD v4.1
  • insufficient to assess BS2.
Still missing
  • No phenotype data for gnomAD carriers.
BS3 No well-established functional studies demonstrating no damaging effect for NM_000455.5:c.112C>G (p.Pro38Ala) were identified. No publications with functional characterization of this specific variant were found. Details ▾Hide ▴
Evidence considered
  • No variant-specific functional studies available.
Still missing
  • No functional data for this variant.
BS4 No segregation data are available to assess lack of segregation with disease. No family studies were identified for NM_000455.5:c.112C>G. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family segregation studies.
BP2 No observation of NM_000455.5:c.112C>G in trans with a known pathogenic STK11 variant was identified. No phase data are available from gnomAD or the literature. Details ▾Hide ▴
Evidence considered
  • No observation in trans with a pathogenic variant.
Still missing
  • No phase or trans observation data.
BP5 No cases have been identified where an individual carrying NM_000455.5:c.112C>G has an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis identified in variant carriers.
Still missing
  • No clinical data for variant carriers.
BP6 No reputable source has classified NM_000455.5:c.112C>G as benign. All ClinVar entries are VUS. No expert panel benign classification is available. Details ▾Hide ▴
Evidence considered
  • ClinVar consensus: VUS
  • no authoritative benign classification.
Still missing
  • No authoritative benign classification available.
Sources
clinvar ↗
PS5 No expert panel or reputable source has classified NM_000455.5:c.112C>G as pathogenic. All ClinVar submissions classify the variant as Uncertain Significance from single submitters, which does not meet the threshold for PS5. Details ▾Hide ▴
Evidence considered
  • ClinVar: VUS from 9 single submitters
  • no expert panel classification available.
Still missing
  • No authoritative pathogenic classification.
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000455.5:c.112C>G is a missense variant (p.Pro38Ala), not a null variant. It does not fall into the nonsense, frameshift, or canonical splice consensus categories required for PVS1 application under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
  • Missense variant at codon 38
  • variant_bucket=other
  • apply_generic_pvs1_framework=false.
Sources
pvs1_variant_assessmentpvs1_gene_context
PM3 N/ANo data on observation in trans with a pathogenic variant for a recessive disorder. STK11-associated Peutz-Jeghers syndrome is autosomal dominant. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to non-frameshift deletions/insertions causing protein length change. This variant is a single-nucleotide substitution resulting in a missense change. Details ▾Hide ▴

No further detail was recorded.

PP2 N/APP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease, supported by gene-specific constraint metrics. No HCI prior or missense constraint score is available for STK11 to support PP2 application in the generic ACMG framework. Details ▾Hide ▴
Evidence considered
  • HCI prior not available
  • no gene-specific missense constraint metric.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This variant is a single-nucleotide substitution. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene
STK11
Transcript
NM_000455.5
Coding (HGVS c.)
NM_000455.5:c.112C>G
Protein (HGVS p.)
NP_000446.1:p.(Pro38Ala)
GRCh38
chr19:1207025 C>G
GRCh37
chr19:1207024 C>G
ClinVar
458014

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 9 / 1,613,804 alleles AF 5.58e-06 · 0 homozygotes · FAF 2.47e-06
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 0 / 0 alleles AF 0 · 0 homozygotes · FAF 0

By genetic ancestry

gnomAD v4.1

AF 5.6e-06 · 9 / 1,613,804 alleles · 0 hom · FAF 2.5e-06
European (Finnish)2 / 63,958 3.1e-05
European (non-Finnish)7 / 1,179,868 5.9e-06
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD-Canada

AF 0 · 0 / 0 alleles · 0 hom

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 5.57689e-06; MAF= 0.00056%, 9/1613804 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.12705e-05; MAF= 0.00313%, 2/63958 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

Open the gnomAD-Canada detail page →

SpliceAI and Pangolin

Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.010

Other predictors

REVEL
0.328
BayesDel
-0.085

How the predictions were used

BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splice impact (max delta = 0.0). REVEL score is 0.328, below pathogenic thresholds. BayesDel score is -0.085 (negative, favoring a benign interpretation). These findings meet BP4 at supporting benign level. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.0
  • REVEL=0.328
  • BayesDel=-0.085 (favoring benign).
Sources
spliceai ↗revelbayesdel
PP3 Multiple in silico tools do not support a deleterious effect for NM_000455.5:c.112C>G (p.Pro38Ala). SpliceAI predicts no splice impact (max delta = 0.0). REVEL score is 0.328, below commonly used pathogenic thresholds (>0.5). BayesDel score is -0.085 (negative, favoring a benign interpretation). Multiple lines of computational evidence do not support pathogenicity. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.0
  • REVEL=0.328
  • BayesDel=-0.085.
Sources
spliceai ↗revelbayesdel
BP7 BP7 applies to synonymous variants with no predicted splice impact. NM_000455.5:c.112C>G is a missense variant (p.Pro38Ala), resulting in a non-conservative amino acid substitution from proline to alanine. BP7 does not apply to missense variants. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 criteria require a synonymous variant.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.328. BayesDel score = -0.0851511.

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

  • ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes.
    Syngal S et al. · 2015
    No paper-specific finding is recorded.
    PMID 25645574 ↗
  • 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.
    PMID 25741868 ↗
  • 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.
    PMID 31672839 ↗
  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    No paper-specific finding is recorded.
    PMID 15604628 ↗
  • Peutz-Jeghers Syndrome.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301443 ↗
  • ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
    Green RC et al. · 2013
    No paper-specific finding is recorded.
    PMID 23788249 ↗
  • ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing.
    ACMG Board of Directors · 2015
    No paper-specific finding is recorded.
    PMID 25356965 ↗
  • 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. · 2015
    No paper-specific finding is recorded.
    PMID 25394175 ↗
  • 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 9 / 1,613,804 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.000 Open source ↗
ClinVar 7 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

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= 5.57689e-06; MAF= 0.00056%, 9/1613804 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.12705e-05; MAF= 0.00313%, 2/63958 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.

gnomAD v2.1

Absent from gnomAD v2.1.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 458014)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.328. BayesDel score = -0.0851511.

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.