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STK11c.*9G>AUncertain significance
Print report
Variant interpretation report

STK11 c.*9G>A, p.?

NM_000455.5:c.*9G>A NP_000446.1:p.? 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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

NM_000455.5:c.*9G>A is absent from gnomAD v2.1 (0/109,868 alleles) and present at an extremely low frequency in gnomAD v4.1 (9/1,511,712 alleles; AF=0.00006%), well below the 0.1% threshold for PM2. The variant is also absent from gnomAD-Canada v1.0.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

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; combination = 1 supporting, 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.

gnomAD v4.1
gnomAD v2.1
Population frequency
9 / 1,511,712 alleles

gnomAD v4.1: 9 / 1,511,712 alleles. Recorded AF 5.95351e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/109868 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/5302 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.000 maximum delta

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

No listed criterion applied SpliceAI ↗
ClinVar submissions
7 reported laboratory submissions

3 Likely benign · 3 Uncertain significance · 1 Benign. ClinVar API review status: criteria provided, conflicting classifications.

Context only ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded

No standalone functional evidence summary is recorded in evidence_summary.functional.

No listed criterion applied OncoKB ↗
No screenshot for this evidence
Somatic evidence
Not assessed

No COSMIC evidence statement is recorded in this case.

Context only
For specialists

Technical detail

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

26 criteria with recorded statuses: 1 met · 17 not met · 0 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000455.5:c.*9G>A is a 3' UTR variant in STK11 located 9 nucleotides downstream of the stop codon.

The variant is absent from gnomAD v2.1 (0/109,868 alleles) and present at extremely low frequency in gnomAD v4.1 (9/1,511,712 alleles; AF=0.00006%), supporting application of PM2 at supporting strength.

ClinVar lists this variant under ID 387684 with mixed classifications (Likely benign from 3 laboratories, Uncertain significance from 3 laboratories, Benign from 1 laboratory) at 1-star review status, which does not meet the 3-star threshold for PP5 or BP6.

No functional studies, segregation data, de novo observations, case-control data, or phenotype information are available for this variant. No published literature mentions NM_000455.5:c.*9G>A specifically.

SpliceAI predicts no splicing impact (max delta score = 0.00), consistent with a benign splicing effect, though insufficient alone to meet BP4.

With only one pathogenic criterion met at supporting strength (PM2) and no benign criteria met, the evidence is insufficient to classify this variant beyond Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules.

Met · 1

PM2 SupportingNM_000455.5:c.*9G>A is absent from gnomAD v2.1 (0/109,868 alleles) and present at an extremely low frequency in gnomAD v4.1 (9/1,511,712 alleles; AF=0.00006%), well below the 0.1% threshold for PM2. The variant is also absent from gnomAD-Canada v1.0. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1: 0/109
  • 868 alleles (AF=0%)
  • gnomAD v4.1: 9/1
  • 511
  • 712 alleles (AF=5.95e-06
  • 0.00006%)
  • grpmax FAF=2.57e-06
  • gnomAD-Canada: absent.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 17 · evaluated, threshold not reached

PS2 No de novo observation has been reported for NM_000455.5:c.*9G>A in any reviewed source. De novo status cannot be assessed without confirmed parent-of-origin testing for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data found in ClinVar submissions
  • publications
  • or literature review.
Still missing
  • No parental testing data available.
PS3 No functional studies have been performed on NM_000455.5:c.*9G>A. The variant is located in the 3' UTR and has not been directly tested in any experimental system, nor does it fall within a systematically characterized range in any functional study. Details ▾Hide ▴
Evidence considered
  • No functional data in evidence_brief (COSMIC negative
  • OncoKB negative
  • no hotspot data). No variant-specific functional studies identified in literature.
Still missing
  • No functional characterization of this 3' UTR variant exists.
PS4 No case-control or prevalence data are available comparing the frequency of NM_000455.5:c.*9G>A in affected individuals versus controls. The available literature consists of clinical practice guidelines and review articles that do not report variant-specific case observations. Details ▾Hide ▴
Evidence considered
  • No case counts or odds ratios identified in ClinVar or publications
  • guideline papers reviewed (PMID:25394175
  • PMID:27854360) contain no variant-specific case data.
Still missing
  • No affected-vs-control frequency data for this variant.
PM1 The variant is located in the 3' UTR (c.*9), 9 nucleotides downstream of the stop codon. No evidence establishes this specific nucleotide position as a critical functional domain, mutational hotspot, or well-characterized regulatory element in STK11. No cancerhotspots.org listing exists for this variant. Details ▾Hide ▴
Evidence considered
  • 3' UTR position
  • no domain-level annotation
  • hotspots: residue_significant=false
  • exact_variant_listed=no.
Still missing
  • No characterization of whether the c.*9 position lies within a functionally validated 3' UTR regulatory element.
PM6 No de novo observation of NM_000455.5:c.*9G>A with confirmed parentage has been reported. Review of available full-text publications confirms no variant-specific de novo finding. Details ▾Hide ▴
Evidence considered
  • No de novo reports in ClinVar submissions or reviewed full-text articles.
Still missing
  • No parental testing data for any proband carrying this variant.
PP1 No cosegregation data are available for NM_000455.5:c.*9G>A. None of the reviewed publications report family studies with this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data in any source.
Still missing
  • No family segregation analysis available.
PP3 No in silico predictors support a damaging effect. REVEL and BayesDel scores are not available for this 3' UTR variant. SpliceAI predicts no splicing impact (max delta score = 0.00). No HCI prior score exists for STK11 3' UTR positions. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00 (no splicing impact)
  • REVEL/BayesDel not applicable (3' UTR)
  • HCI prior: gene_not_supported for STK11.
Still missing
  • No in silico tools designed for 3' UTR functional prediction are available/assessed.
Sources
spliceai ↗
PP4 No patient phenotype or clinical data are available for individuals carrying NM_000455.5:c.*9G>A. The variant's phenotype specificity for Peutz-Jeghers syndrome or other STK11-associated conditions cannot be evaluated. Details ▾Hide ▴
Evidence considered
  • No phenotype data in evidence_brief
  • publications
  • or ClinVar submissions.
Still missing
  • No clinical phenotype information for carriers of this variant.
PP5 ClinVar reports NM_000455.5:c.*9G>A as Likely benign (3 labs), Uncertain significance (3 labs), and Benign (1 lab) under variation ID 387684. The review status is 'criteria provided, single submitter' (1 star), which does not meet the 3-star expert panel threshold required for PP5 application. Furthermore, the ClinVar aggregate classification is Likely benign, not pathogenic. Details ▾Hide ▴
Evidence considered
  • ClinVar 387684: Likely benign (3 labs LB
  • 3 labs VUS
  • 1 lab B)
  • 1-star review status
  • no expert panel submissions.
Sources
clinvar ↗
BA1 The maximum allele frequency of NM_000455.5:c.*9G>A in gnomAD is 0.00006% (gnomAD v4.1, 9/1,511,712 alleles), far below the 1% threshold required for BA1. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF=0%
  • gnomAD v4.1 AF=5.95e-06 (0.00006%)
  • both far below 1% BA1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 The allele frequency of NM_000455.5:c.*9G>A is 0.00006% (gnomAD v4.1), far below the 0.3% threshold required for BS1. Details ▾Hide ▴
Evidence considered
  • gnomAD v2.1 AF=0%
  • gnomAD v4.1 AF=5.95e-06
  • both far below 0.3% BS1 threshold.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 NM_000455.5:c.*9G>A has not been observed in a homozygous state in gnomAD (0 homozygotes in both v2.1 and v4.1). No evidence exists that this variant has been observed in healthy adults at a frequency inconsistent with pathogenicity. Details ▾Hide ▴
Evidence considered
  • gnomAD: 0 homozygotes
  • total allele count 9 in v4.1
  • extremely rare
  • no data supporting observation in healthy adults at high frequency.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS3 No functional studies demonstrating a benign effect have been performed on NM_000455.5:c.*9G>A. The variant has not been tested in any experimental system. Details ▾Hide ▴
Evidence considered
  • No functional data available
  • COSMIC negative
  • OncoKB negative
  • no variant-specific functional studies identified.
Still missing
  • No functional characterization exists for this 3' UTR variant.
BS4 No segregation data are available for NM_000455.5:c.*9G>A to evaluate lack of segregation with disease. Details ▾Hide ▴
Evidence considered
  • No family studies or segregation data available.
Still missing
  • No segregation analysis available.
BP2 No data are available regarding observation of NM_000455.5:c.*9G>A in trans with a known pathogenic STK11 variant. Details ▾Hide ▴
Evidence considered
  • No phase data or co-occurrence data with pathogenic STK11 variants in any source.
Still missing
  • No phase information available.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. The only applicable in silico tool for this 3' UTR variant is SpliceAI, which predicts no splicing impact (max delta = 0.00). However, a single line of computational evidence is insufficient to meet the 'multiple lines' requirement. REVEL and BayesDel are not available for 3' UTR positions, and no conservation data were assessed. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00 (benign)
  • REVEL/BayesDel not applicable
  • insufficient for 'multiple lines' requirement.
Still missing
  • No conservation or regulatory prediction data available for this 3' UTR position.
Sources
spliceai ↗
BP6 ClinVar reports NM_000455.5:c.*9G>A as Likely benign (3 labs), Uncertain significance (3 labs), and Benign (1 lab). However, the review status is 'criteria provided, single submitter' (1 star), which falls below the 3-star expert panel threshold required to apply BP6 at supporting benign strength. Details ▾Hide ▴
Evidence considered
  • ClinVar 387684: mixed classifications (LB/VUS/B)
  • 1-star review status
  • 0 expert panel submissions
  • does not meet 3-star EP threshold for BP6.
Sources
clinvar ↗
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000455.5:c.*9G>A is a 3' UTR substitution located 9 nucleotides downstream of the stop codon. It does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The PVS1 decision tree confirms the variant does not trigger generic PVS1 assessment. Details ▾Hide ▴
Evidence considered
  • Variant is c.*9G>A in the 3' UTR
  • not a null variant
  • PVS1 variant assessment returns apply_generic_pvs1_framework=false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS1 N/APS1 requires a different nucleotide change at the same position with a known pathogenic classification and a more severe predicted consequence. This variant is in the 3' UTR where there is no amino acid consequence hierarchy; no known pathogenic variant exists at c.*9 of STK11. Details ▾Hide ▴
Evidence considered
  • Variant is in the 3' UTR
  • amino acid change paradigm does not apply
  • no pathogenic comparator at c.*9 in ClinVar.
PM5 N/APM5 requires a different pathogenic missense change at the same codon. NM_000455.5:c.*9G>A is in the 3' UTR, not within the coding sequence; no codon position exists. PM5 candidate harvesting confirmed no eligible comparators. Details ▾Hide ▴
Evidence considered
  • 3' UTR variant
  • pm5_candidates: eligible_for_classic_pm5_search=false
  • no same-residue candidates identified.
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes where missense variation is a known mechanism and benign missense variation is rare. NM_000455.5:c.*9G>A is a 3' UTR variant, not a missense change. Details ▾Hide ▴
Evidence considered
  • Variant is in the 3' UTR
  • PP2 is specific to missense variants.
BP1 N/ABP1 is specific to missense variants in genes where a truncating mechanism is established. NM_000455.5:c.*9G>A is a 3' UTR substitution and does not produce a missense change. Details ▾Hide ▴
Evidence considered
  • Variant is in the 3' UTR
  • BP1 is restricted to missense variants.
BP5 N/ABP5 applies when a variant is found in a case with an alternate molecular basis for disease. No such data exist, and this criterion is not applicable to the current assessment. Details ▾Hide ▴
Evidence considered
  • No alternate molecular basis identified
  • variant-specific assessment impossible without clinical context.
BP7 N/ABP7 applies to synonymous (silent) coding variants with no predicted splicing impact. NM_000455.5:c.*9G>A is a 3' UTR variant, not a synonymous coding variant. Details ▾Hide ▴
Evidence considered
  • Variant is in the 3' UTR (c.*9)
  • BP7 is restricted to synonymous coding variants.
PS5 N/APS5 applies when a different pathogenic missense change has been identified at the same amino acid position. NM_000455.5:c.*9G>A is a 3' UTR variant with no amino acid change (p.(=)); the paradigm does not apply. Details ▾Hide ▴
Evidence considered
  • Variant is in the 3' UTR
  • no amino acid position to compare
  • PS5 is restricted to coding missense changes.

Identifiers

Gene
STK11
Transcript
NM_000455.5
Coding (HGVS c.)
NM_000455.5:c.*9G>A
Protein (HGVS p.)
NP_000446.1:p.?
GRCh38
chr19:1226656 G>A
GRCh37
chr19:1226655 G>A
ClinVar
387684

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 / 1,511,712 alleles AF 5.95e-06 · 0 homozygotes · FAF 2.57e-06
gnomAD v2.1 0 / 109,868 alleles AF 0 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6e-06 · 9 / 1,511,712 alleles · 0 hom · FAF 2.6e-06
Admixed American1 / 44,786 2.2e-05
South Asian1 / 80,202 1.2e-05
European (non-Finnish)7 / 1,132,220 6.2e-06
0 alternate alleles recorded in 7 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 0 · 0 / 109,868 alleles · 0 hom
No alternate alleles recorded in the displayed ancestry groups.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 5.95351e-06; MAF= 0.00060%, 9/1511712 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.23284e-05; MAF= 0.00223%, 1/44786 alleles, homozygotes = 0); grpmax FAF= 2.57e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/109868 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/5302 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -146 bp
0.000
SpliceAI acceptor gainat -197 bp
0.000
SpliceAI donor lossat +69 bp
0.000
SpliceAI donor gainat -13 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.020

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 No in silico predictors support a damaging effect. REVEL and BayesDel scores are not available for this 3' UTR variant. SpliceAI predicts no splicing impact (max delta score = 0.00). No HCI prior score exists for STK11 3' UTR positions. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00 (no splicing impact)
  • REVEL/BayesDel not applicable (3' UTR)
  • HCI prior: gene_not_supported for STK11.
Still missing
  • No in silico tools designed for 3' UTR functional prediction are available/assessed.
Sources
spliceai ↗
BP4 BP4 requires multiple lines of computational evidence suggesting no impact. The only applicable in silico tool for this 3' UTR variant is SpliceAI, which predicts no splicing impact (max delta = 0.00). However, a single line of computational evidence is insufficient to meet the 'multiple lines' requirement. REVEL and BayesDel are not available for 3' UTR positions, and no conservation data were assessed. Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta=0.00 (benign)
  • REVEL/BayesDel not applicable
  • insufficient for 'multiple lines' requirement.
Still missing
  • No conservation or regulatory prediction data available for this 3' UTR position.
Sources
spliceai ↗
BP7 N/ABP7 applies to synonymous (silent) coding variants with no predicted splicing impact. NM_000455.5:c.*9G>A is a 3' UTR variant, not a synonymous coding variant. Details ▾Hide ▴
Evidence considered
  • Variant is in the 3' UTR (c.*9)
  • BP7 is restricted to synonymous coding variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

7 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
    Clinical practice guideline from the American College of Gastroenterology on hereditary gastrointestinal cancer syndromes, including Peutz-Jeghers syndrome associated with STK11. Discusses diagnostic criteria and management recommendations at the gene/syndrome level. NM_000455.5:c.*9G>A is not mentioned.
    Does not name this variant
    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.
    ACMG/AMP consensus guidelines for sequence variant interpretation. Provides the generic classification framework and criteria definitions. No variant-specific content; NM_000455.5:c.*9G>A is not discussed.
    Does not name this variant
    PMID 25741868 ↗
  • A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
    Describes a standardized rules-based DNA variant scoring system for Mendelian disorders. Analyzed over 16,500 pathogenicity assessments across 338 genes. NM_000455.5:c.*9G>A is not discussed.
    Does not name this variant
    PMID 26467025 ↗
  • 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
    ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. Lists Peutz-Jeghers syndrome and STK11 in syndromic referral criteria tables. NM_000455.5:c.*9G>A is not mentioned or discussed.
    Does not name this variant
    PMID 25394175 ↗
  • Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ Cancer Genetics Risk Assessment and Counseling summary (Health Professional Version). Provides general cancer genetics counseling guidance. NM_000455.5:c.*9G>A is not mentioned.
    Does not name this variant
    PMID 26389258 ↗
  • Genetics of Colorectal Cancer (PDQ®): Health Professional Version.
    PDQ Cancer Genetics Editorial Board · 2002
    PDQ Genetics of Colorectal Cancer summary (Health Professional Version). Covers hereditary colorectal cancer syndromes including Peutz-Jeghers syndrome at the gene level. NM_000455.5:c.*9G>A is not mentioned.
    Does not name this variant
    PMID 26389505 ↗
  • Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics.
    Kalia SS et al. · 2017
    ACMG SF v2.0 policy statement on secondary findings reporting in clinical genomic sequencing. STK11 is listed in the secondary findings gene table for Peutz-Jeghers syndrome. NM_000455.5:c.*9G>A is not mentioned.
    Does not name this variant
    PMID 27854360 ↗

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

gnomAD v4.1 9 / 1,511,712 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 3 Likely benign · 3 Uncertain significance · 1 Benign 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= 5.95351e-06; MAF= 0.00060%, 9/1511712 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.23284e-05; MAF= 0.00223%, 1/44786 alleles, homozygotes = 0); grpmax FAF= 2.57e-06.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 0; MAF= 0.00000%, 0/109868 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/5302 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Likely benign (3 clinical laboratories) and as Uncertain significance (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 387684)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).