Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
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.
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.
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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.
Met (supporting): grpmax FAF 4.13e-06 (gnomAD v2.1) is well below the <=0.0001 PM2 rarity threshold.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Met (supporting): SpliceAI max delta 0.01 versus the <=0.1 BP4 supporting threshold.
Recorded classification: Uncertain significance
VUS: PM2 (supporting) plus BP4 (supporting) form one supporting pathogenic against one supporting benign criterion, matching no ACMG/AMP 2015 combination rule.
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
33 / 1,575,088 alleles
gnomAD v4.1: 33 / 1,575,088 alleles. Recorded AF 2.09512e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.06659e-05; MAF= 0.00107%, 2/187514 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.49054e-05; MAF= 0.00249%, 2/80304 alleles, homozygotes = 0); grpmax FAF= 4.13e-06.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 9 not met · 7 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
PVS1 is not applicable to NM_000455.5:c.-1C>T: the variant is a 5' UTR substitution upstream of the initiation codon (Mutalyzer/VariantValidator outside_cds = upstream; exon 1 exonic), and PVS1 covers only predicted-null classes (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, exon-level deletion).
The gene-level precondition for PVS1 is satisfied for STK11 (germline loss of function/haploinsufficiency causes Peutz-Jeghers syndrome), but the variant itself is not a null allele.
The variant is not a canonical splice variant: it lies ~291 bp inside exon 1 (c.-1136 to c.290) of NM_000455.5, and SpliceAI predicts no splice effect (max delta 0.01, well below the >=0.2 supporting cut-off), so there is no splice-null to convert into a reduced-strength PVS1 call.
No SVI/VCEP downgrade rule was applied because the criterion is not met at any strength; no gene-specific STK11 specification exists, so the generic ACMG/AMP 2015 + ClinGen SVI PVS1 framework governs.
Functional group evaluated PS3 and BS3 only, under generic ACMG/AMP 2015 criteria because no STK11-specific VCEP/ClinGen CSPEC specification is available in this case.
No functional assay (minigene, transcript/RT-PCR, protein or kinase-activity, mRNA stability) has been performed on STK11 c.-1C>T in the assembled evidence, so neither a damaging (PS3) nor a non-damaging (BS3) functional effect can be established.
SpliceAI max delta score 0.01 is computational and belongs to the PP3/BP4 path, not to PS3/BS3; COSMIC somatic count 1 and the conflicting ClinVar classifications are also not functional evidence.
Both criteria are therefore not_assessed, with the documented gap being the absence of any functional assay for this variant.
None of the five phenotype/prevalence/assertion criteria are met for NM_000455.5(STK11):c.-1C>T.
PS4: no affected-vs-control or case-control enrichment data exist for this variant.
PP4: no proband phenotype or family history is available to assess disease specificity.
PP5 and BP6: ClinVar record 185127 is laboratory-only (0 expert-panel submissions, 1-star conflicting review status), so neither expert-panel assertion criterion is triggered.
BP5: no case carrying this variant has a documented alternative molecular basis for disease.
The allelic group contributes no evidence for this variant: PM3 is not applicable because STK11-related Peutz-Jeghers syndrome is autosomal dominant, and BP2 could not be assessed because the case contains no second STK11 variant, proband genotype, or phasing data.
Both criteria depend on a companion (likely) pathogenic STK11 allele with known phase; no such allele is present in this variant-level case.
PP3 and BP4 were evaluated on the SpliceAI path only, selected by the variant's own consequence: NM_000455.5:c.-1C>T is a splice-region/non-missense change (consequence class canonical_splice, protein NP_000446.1:p.?), so the REVEL/BayesDel missense path is out of scope regardless of score availability.
SpliceAI max delta score 0.01 is below the >=0.2 supporting PP3 cutoff (PP3 not met) and at or below the <=0.1 BP4 supporting cutoff (BP4 met at supporting strength).
No gene-specific STK11 specification exists (ClinGen CSPEC not found; no VCEP framework), so the generic ACMG/AMP 2015 framework and published SpliceAI cutoffs (Jaganathan et al. 2019, PMID:30661751) govern.
REVEL and BayesDel were unavailable (not found); neither would have been applicable to this non-missense variant.
The population criteria were assessed under the generic ACMG/AMP 2015 framework because no ClinGen CSPEC or VCEP specification (and no local gene-specific framework) exists for STK11 in this case.
The governing specification does not mandate a non-cancer/exome-only population source, so the all-comers gnomAD v2.1 and v4.1 totals were used by default; the provided non-cancer subsets (GNOMAD_V2_1_NON_CANCER exomes, GNOMAD_V3_1_NON_CANCER genomes) were reviewed and give likewise extremely rare frequencies.
BA1 (>=0.05) and BS1 (>=0.01) are not met: the maximum frequency in any population (gnomAD v4.1 'Remaining individuals', 1.14664e-04) is roughly 435-fold and 87-fold below the respective thresholds, with no homozygotes.
BS2 is not met: no homozygotes were observed and STK11/Peutz-Jeghers syndrome is an incompletely penetrant, adult-onset autosomal dominant condition, so the BS2 premise of full penetrance at an early age is not satisfied.
PM2 is met at supporting strength: all gnomAD frequencies (grpmax FAF 4.13e-06 v2.1 and 1.558e-05 v4.1; total AF 1.07e-05-2.10e-05) sit at or below the <=0.0001 supporting threshold.
No criteria match.
Met · 2
PM2SupportingMet (supporting): grpmax FAF 4.13e-06 (gnomAD v2.1) is well below the <=0.0001 PM2 rarity threshold.
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Reasoning
The variant is extremely rare in every population dataset examined, consistent with PM2 supporting evidence. No STK11 VCEP/CSPEC specification exists, so the default all-comers gnomAD totals apply and the non-cancer subsets were also checked. gnomAD v2.1 (all-comers): total AF 1.06659e-05 (2/187514 alleles), grpmax FAF 4.13e-06, homozygotes 0. gnomAD v4.1 (all-comers): total AF 2.09512e-05 (33/1575088 alleles), grpmax FAF 1.558e-05, homozygotes 0. gnomAD v2.1 non-cancer exomes: AF 1.10894e-05 (2/180352). gnomAD v3.1 non-cancer genomes: AF 6.77021e-06 (1/147706). Every figure is at or below the supporting PM2 threshold of <= 0.0001, and no homozygotes were observed. PM2 is met at supporting strength in line with the ClinGen SVI recommendation to downgrade PM2 to Supporting.
Rule
PM2: supporting pathogenic, allele frequency <= 0.0001 (ClinGen SVI 2020 downgrade of PM2 to supporting, PMID:25741868); generic ACMG fallback (no STK11 VCEP/CSPEC).
Evidence considered
gnomAD v2.1 (all-comers): total AF 1.06659e-05 (2/187514), grpmax FAF 4.13e-06, homozygotes 0.
gnomAD v4.1 (all-comers): total AF 2.09512e-05 (33/1575088), grpmax FAF 1.558e-05, homozygotes 0; highest population 'Remaining individuals' 1.14664e-04.
gnomAD v2.1 non-cancer exomes: AF 1.10894e-05 (2/180352), homozygotes 0.
gnomAD v3.1 non-cancer genomes: AF 6.77021e-06 (1/147706), homozygotes 0.
gnomAD-Canada v1.0 returned no data (timeout); not relied upon.
Threshold applied: PM2 supporting rarity <= 0.0001 (ClinGen SVI 2020 recommendation to downgrade PM2 to Supporting; PMID:25741868).
BP4SupportingMet (supporting): SpliceAI max delta 0.01 versus the <=0.1 BP4 supporting threshold.
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Reasoning
Same scope decision as PP3: NM_000455.5:c.-1C>T is a splice-region variant (consequence class canonical_splice; non-missense, non-synonymous), so BP4 is evaluated on the SpliceAI path only. SpliceAI max delta score is 0.01 (DS_AG 0.0, DS_AL 0.01, DS_DG 0.001, DS_DL 0.001), at or below the <=0.1 BP4 supporting cutoff (Jaganathan et al. 2019, Cell; PMID:30661751), so computational evidence predicts no impact on splicing and BP4 is met at supporting strength. No stronger BP4 tier is supported by this score, and the missense path is not a fallback: REVEL and BayesDel were not available and BP4 is not derived from them. No STK11 VCEP/CSPEC specification exists (ClinGen CSPEC not found; framework_mode generic_acmg), so the generic threshold applies. The single SpliceAI prediction is not double-counted across PP3/BP4/BP7.
Rule
BP4_spliceai_max_delta<=0.1
Evidence considered
SpliceAI lookup for NM_000455.5:c.-1C>T (hg37) returned max delta score 0.01, at or below the <=0.1 BP4 supporting cutoff (Jaganathan et al. 2019, Cell; PMID:30661751).
BP4 taken from the SpliceAI (splice) path only, matched to the variant's canonical_splice consequence class; no evidence was drawn from the REVEL/BayesDel missense path.
No ClinGen CSPEC or VCEP/gene-specific PP3/BP4 lookup specification exists for STK11 (vcep_materials.json found=false; framework_mode generic_acmg), so no pre-assigned VCEP code overrides the generic cutoff.
The same SpliceAI prediction is not reused to satisfy PP3, BP7, or any other criterion.
PS4Not met: no case-control enrichment data exist for this variant, and the only STK11 case series does not name c.-1C>T.
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Reasoning
PS4 (Richards et al. 2015, PMID:25741868) requires that the prevalence of this exact variant be significantly increased in affected individuals compared with controls. No case-control or affected-vs-control cohort data exist for NM_000455.5(STK11):c.-1C>T. The ClinVar record VCV000185127 contains only eight ordinary clinical-laboratory submissions (four Uncertain significance, three Likely benign, one Benign) with no case-control design and no affected or control counts, and the only STK11 case observation identified (Yurgelun et al. 2015, PMID:25980754, one individual carrying a pathogenic STK11 variant alongside a pathogenic MSH6 variant) does not name this nucleotide change, so it provides no variant-level enrichment signal. gnomAD shows only 2 alleles (v2.1) and 33 alleles (v4.1) worldwide with zero homozygotes, consistent with an absence of reported case enrichment. With no odds ratio or comparable enrichment statistic available for this variant, PS4 is not met.
Evidence considered
ClinVar VCV000185127 (variation 185127): 8 clinical-laboratory submissions with no case-control design or affected/control counts.
PMID:25980754 (Yurgelun et al. 2015): multigene panel testing in 1260 individuals with suspected Lynch syndrome; one subject carried pathogenic STK11 and MSH6 variants, but the STK11 alteration is unnamed and c.-1C>T is not reported.
gnomAD v2.1 and v4.1: 2 and 33 alleles respectively, zero homozygotes, no signal of affected-cohort enrichment.
Still missing
No genotype-matched case-control or affected-vs-control cohort data exist for c.-1C>T; such a study would be required to apply PS4.
PP3Not met: SpliceAI max delta 0.01, far below the >=0.2 supporting PP3 threshold.
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Reasoning
NM_000455.5:c.-1C>T is a splice-region variant in STK11 (consequence class canonical_splice; a non-missense, non-synonymous substitution one base upstream of the initiation codon, predicted protein NP_000446.1:p.?), so PP3 takes computational evidence from the SpliceAI path only, never from REVEL/BayesDel. SpliceAI max delta score is 0.01 (DS_AG 0.0, DS_AL 0.01, DS_DG 0.001, DS_DL 0.001), below both the >=0.2 supporting and >=0.5 moderate PP3 cutoffs (Jaganathan et al. 2019, Cell; PMID:30661751), so no splice-altering effect is predicted and PP3 is not met. No STK11 VCEP/CSPEC specification exists (ClinGen CSPEC not found; framework_mode generic_acmg), so the generic SpliceAI thresholds apply. REVEL and BayesDel were not available (both null/not found) and would not be applicable to a non-missense variant in any case.
Rule
PP3_spliceai_max_delta>=0.2
Evidence considered
SpliceAI lookup for NM_000455.5:c.-1C>T (hg37) returned max delta score 0.01 with all component deltas <=0.01 (DS_AG 0.0, DS_AL 0.01, DS_DG 0.001, DS_DL 0.001); Pangolin SG 0.002 / SL -0.008.
Path selection: the variant's own consequence class is canonical_splice (splice-region; non-missense, non-synonymous), so only the SpliceAI path contributes to PP3/BP4; the REVEL/BayesDel (missense) path is inapplicable.
Governing specification: no ClinGen CSPEC and no VCEP/gene-specific framework is available for STK11 (vcep_materials.json found=false, framework_mode generic_acmg), so the generic ACMG/AMP 2015 framework and the published SpliceAI cutoffs (Jaganathan et al. 2019, PMID:30661751) apply.
REVEL and BayesDel were queried and were not found (score null), so the missense calibration could not be and need not be applied.
No double-counting: the same SpliceAI prediction is not reused to support PVS1 or any other criterion.
PP4Not met: no proband phenotype or family history is available to demonstrate disease specificity for this variant.
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Reasoning
PP4 (Richards et al. 2015, PMID:25741868) requires that the patient's phenotype or family history be highly specific for a disease with a single genetic etiology. This case is assessed at the variant level and no proband phenotype or family history is recorded anywhere in the available evidence. The ClinVar record lists multiple, non-specific conditions for this variant (breast and/or ovarian cancer, hereditary cancer-predisposing syndrome, Peutz-Jeghers syndrome, STK11-related disorder, not provided, not specified), which does not establish a single highly specific disease presentation attributable to the individual carrying c.-1C>T. The STK11-Peutz-Jeghers syndrome association is a gene-level relationship (PMID:20301443) and cannot substitute for an individual's phenotype. With no patient-level phenotype to evaluate, phenotype specificity is not demonstrated and PP4 is not met.
Evidence considered
No proband phenotype or family history for c.-1C>T is recorded in the case evidence.
ClinVar lists several distinct, non-specific conditions for this variant rather than one highly specific disease presentation.
PMID:20301443 (Peutz-Jeghers Syndrome GeneReview) establishes the STK11-PJS gene-level association but provides no data on this variant or on a specific proband's phenotype.
PMID:35802134 (ACMG SF v3.1) lists STK11 under Peutz-Jeghers syndrome (OMIM 175200, autosomal dominant) as a gene-level phenotype association only.
Still missing
No proband phenotype or family history is provided; individual-level clinical data are required to assess phenotype specificity under PP4.
PP5Not met: ClinVar record 185127 has 0 expert-panel submissions and a conflicting, 1-star laboratory-only review status.
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Reasoning
PP5 requires a pathogenic or likely pathogenic classification of this exact variant from a recognized expert panel. ClinVar record VCV000185127 for NM_000455.5(STK11):c.-1C>T has no expert-panel submission: the expert-panels object is empty, the expert-panel submission count is 0, and all eight submitters are ordinary clinical laboratories (Quest Diagnostics, CHEO Genetics, Ambry Genetics, LabCorp, Color Health, Genome-Nilou, GeneDx and PreventionGenetics). The record's review status is 'criteria provided, conflicting classifications' (1 star, laboratory submissions only) and its overall interpretation is Uncertain significance. Because aggregate or non-expert laboratory assertions must never trigger PP5, and no exact-variant expert-panel pathogenic assertion exists, PP5 is not met.
Expert-panel submissions: 0; expert_panels object empty; all 8 submitters are clinical laboratories (Quest, CHEO, Ambry, LabCorp, Color, Genome-Nilou, GeneDx, PreventionGenetics).
No ClinGen gene-specific specification (CSPEC/VCEP) was found for STK11, and the 4 Uncertain significance / 3 Likely benign / 1 Benign split reflects conflicting laboratory, not expert-panel, interpretations.
Still missing
A recognized expert-panel (e.g. ClinGen VCEP) pathogenic/likely pathogenic classification of this exact variant would be required to apply PP5; none exists.
BA1Not met: maximum population frequency 1.15e-04 (gnomAD v4.1, Remaining individuals) is ~435-fold below the 0.05 BA1 stand-alone threshold.
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Reasoning
No STK11 ClinGen CSPEC/VCEP or local gene-specific framework exists for this case, so the generic ACMG/AMP 2015 stand-alone benign threshold (BA1: allele frequency >= 0.05) applies and the all-comers gnomAD totals are the default population source; the non-cancer subsets were also reviewed and give materially identical, extremely rare results. gnomAD v2.1 (all-comers): total AF 1.06659e-05 (2/187514 alleles, 0 homozygotes), highest population European (non-Finnish) AF 2.49054e-05 (2/80304), grpmax FAF 4.13e-06. gnomAD v4.1 (all-comers): total AF 2.09512e-05 (33/1575088 alleles, 0 homozygotes), highest population 'Remaining individuals' AF 1.14664e-04 (7/61048), grpmax FAF 1.558e-05. gnomAD v2.1 non-cancer exomes: AF 1.10894e-05 (2/180352). gnomAD v3.1 non-cancer genomes: AF 6.77021e-06 (1/147706). The highest frequency observed in any dataset (1.14664e-04) is roughly 435-fold below the 0.05 BA1 threshold, and no homozygotes were observed. BA1 is not met.
Rule
BA1: stand-alone benign, allele frequency >= 0.05 (ACMG/AMP 2015, PMID:25741868); generic ACMG fallback (no STK11 VCEP/CSPEC).
Evidence considered
gnomAD v2.1 (all-comers, GRCh37): total AF 1.06659e-05 (AC 2 / AN 187514), homozygotes 0; highest population European (non-Finnish) AF 2.49054e-05 (2/80304); grpmax FAF 4.13e-06.
gnomAD v4.1 (all-comers, GRCh38): total AF 2.09512e-05 (AC 33 / AN 1575088), homozygotes 0; highest population 'Remaining individuals' AF 1.14664e-04 (7/61048); grpmax FAF 1.558e-05.
gnomAD v2.1 non-cancer exomes: AF 1.10894e-05 (AC 2 / AN 180352), homozygotes 0; NFE AF 2.66446e-05.
gnomAD v3.1 non-cancer genomes: AF 6.77021e-06 (AC 1 / AN 147706), homozygotes 0.
gnomAD-Canada v1.0 lookup returned no result (request timed out); treated as unavailable rather than as an absence.
Threshold applied: BA1 stand-alone allele frequency >= 0.05 (ACMG/AMP 2015, PMID:25741868). No STK11-specific BA1 calibration exists, so the generic stand-alone threshold was used.
BS1Not met: highest subpopulation frequency 1.15e-04 (gnomAD v4.1, Remaining individuals) is ~87-fold below the 0.01 BS1 threshold.
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Reasoning
No STK11 gene-specific framework or frequency calibration exists, so the generic BS1 strong-benign threshold (allele frequency >= 0.01) is used against the default all-comers gnomAD totals; the non-cancer subsets were checked and are equally rare. The highest frequency seen in any population is gnomAD v4.1 'Remaining individuals' AF 1.14664e-04 (7/61048), followed by gnomAD v2.1 non-cancer NFE 2.66446e-05 and gnomAD v2.1 all-comers NFE 2.49054e-05 (2/80304); the overall totals are 2.09512e-05 (v4.1, 33/1575088) and 1.06659e-05 (v2.1, 2/187514), with grpmax FAF 1.558e-05 and 4.13e-06 respectively. All values are at least ~87-fold below the 0.01 threshold. BS1 is not met.
Rule
BS1: strong benign, allele frequency >= 0.01 (generic SVI default; per-gene derivation preferred, Whiffin et al. 2017, PMID:28518168); generic ACMG fallback (no STK11 VCEP/CSPEC).
Evidence considered
gnomAD v4.1 (all-comers): total AF 2.09512e-05 (33/1575088); highest population 'Remaining individuals' 1.14664e-04 (7/61048); NFE 2.23938e-05; grpmax FAF 1.558e-05.
gnomAD v2.1 (all-comers): total AF 1.06659e-05 (2/187514); highest population European (non-Finnish) 2.49054e-05 (2/80304); grpmax FAF 4.13e-06.
gnomAD v2.1 non-cancer exomes: AF 1.10894e-05 (2/180352); NFE 2.66446e-05.
gnomAD v3.1 non-cancer genomes: AF 6.77021e-06 (1/147706).
No STK11-specific BS1 threshold is published; the generic SVI default BS1 strong threshold of >= 0.01 (per-gene derivation preferred; Whiffin et al. 2017, PMID:28518168) was applied.
gnomAD-Canada v1.0 returned no data (timeout) and could not contribute a frequency.
Still missing
No STK11-specific BS1 frequency calibration (e.g. gene/disease-prevalence-derived threshold) is published, so the generic 0.01 default was applied.
BS2Not met: zero homozygotes across all gnomAD datasets, and the adult-onset, incompletely penetrant autosomal dominant Peutz-Jeghers phenotype does not satisfy BS2's requirement of full penetrance at an early age.
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Reasoning
BS2 requires the variant to be observed in a healthy adult individual for a disorder with full penetrance expected at an early age. All observed alleles of this variant in gnomAD are heterozygous (gnomAD v2.1: 2/187514; gnomAD v4.1: 33/1575088; non-cancer subsets 2/180352 and 1/147706) and there are zero homozygotes in every dataset. STK11-related Peutz-Jeghers syndrome is an autosomal dominant, cancer-predisposition condition with incomplete, age-dependent penetrance (polyp/cancer phenotypes accrue over decades), not a disorder with full penetrance expected at an early age; therefore heterozygous carrier status in gnomAD adults does not satisfy the BS2 premise, and the absence of any homozygote also removes the recessive interpretation. BS2 is not met.
Rule
BS2: observed in a healthy adult with full penetrance expected at an early age (ACMG/AMP 2015, PMID:25741868); generic ACMG fallback (no STK11 VCEP/CSPEC).
BS2 definition used: observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous) or X-linked disorder with full penetrance expected at an early age (ACMG/AMP 2015, PMID:25741868). STK11/Peutz-Jeghers syndrome is autosomal dominant with incomplete, age-dependent penetrance, so the full-penetrance-at-early-age premise is not satisfied.
Still missing
A quantitative, publication-anchored STK11/Peutz-Jeghers age-specific penetrance estimate was not available in the case evidence to test the BS2 'full penetrance at an early age' premise directly; the criterion was assessed from the inheritance/penetrance profile and the absence of homozygotes.
BP5Not met: no case carrying this variant has a documented alternative molecular cause.
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Reasoning
BP5 (Richards et al. 2015, PMID:25741868) is applied when the variant is found in a case with an alternative molecular basis for the observed disease. No case carrying this exact variant is described with a co-occurring pathogenic variant or another confirmed alternative cause. The only relevant STK11 observation (PMID:25980754) reports one individual with concomitant pathogenic STK11 and MSH6 variants, but the STK11 alteration is unnamed, this c.-1C>T change is not reported, and the co-occurring MSH6 finding cannot be attached to a variant that is not documented in that case. With no case-level co-occurrence or alternative-cause data attributable to c.-1C>T, BP5 is not met.
Evidence considered
No case-level co-occurrence or alternative-cause data for c.-1C>T were identified in the reviewed sources.
PMID:25980754 reports one individual with concomitant pathogenic STK11 and MSH6 variants, but the STK11 variant is unnamed and c.-1C>T is not named in the paper.
Still missing
No case report documents an alternative molecular basis for disease in a carrier of NM_000455.5:c.-1C>T.
BP6Not met: ClinVar record 185127 contains 0 expert-panel submissions; its benign labels are ordinary laboratory assertions.
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Reasoning
BP6 requires a benign or likely benign classification of this exact variant from a recognized expert panel. ClinVar record VCV000185127 for NM_000455.5(STK11):c.-1C>T has no expert-panel submission (expert-panel submission count 0, expert-panels object empty). The three 'Likely benign' and one 'Benign' entries are ordinary clinical-laboratory submissions (Color Health, GeneDx and PreventionGenetics) without expert-panel review, and the record's overall review status is 'criteria provided, conflicting classifications' (1 star), with conflicting laboratory interpretations overall. Because ordinary laboratory assertions and aggregate labels must never trigger BP6, and no exact-variant expert-panel benign assertion exists, BP6 is not met.
Evidence considered
ClinVar VCV000185127: 3 'Likely benign' and 1 'Benign' submissions, all from ordinary clinical laboratories, none expert-panel; review status 'criteria provided, conflicting classifications' (1 star).
Overall ClinVar interpretation for the record is Uncertain significance / conflicting classifications, not an expert-panel benign assertion.
No ClinGen gene-specific specification (CSPEC/VCEP) was found for STK11.
Still missing
A recognized expert-panel benign/likely benign classification of this exact variant would be required to apply BP6; none exists.
PS2Not assessed: zero probands with confirmed parental testing are documented, so a de novo occurrence of c.-1C>T cannot be established.
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Reasoning
PS2 requires a documented de novo occurrence of the variant in an affected proband with confirmed maternity and paternity (Richards et al. 2015, PMID:25741868). NM_000455.5:c.-1C>T (STK11, chr19:g.1206912C>T GRCh37) is a 5' region variant classified by consequence as canonical-splice class, and the case evidence contains no proband, no parental genotypes, no maternity/paternity confirmation and no de novo observation. ClinVar VCV000185127 (variation 185127) holds eight germline submissions with conflicting classifications (4 uncertain significance, 3 likely benign, 1 benign) and no expert-panel submission; none of them reports a de novo event, parental testing or a family. The literature retrieved for this case contains no report of this nucleotide change (all paper extractions record variant_mentioned = false). No STK11-specific CSPEC or VCEP was found, so generic ACMG/AMP 2015 semantics govern and the criterion cannot be assessed on the available evidence.
Evidence considered
ClinVar VCV000185127 (variation 185127) lists eight germline submissions with conflicting classifications (4 uncertain significance, 3 likely benign, 1 benign), review status 'criteria provided, conflicting classifications', no expert-panel submission; no submission documents a de novo occurrence, parental genotypes or a tested family.
The paper extractions assembled for this case (PMID:25741868, PMID:26467025, PMID:25980754, PMID:23788249, PMID:35802134) record variant_mentioned = false for STK11 c.-1C>T; none reports a case, a proband or parental testing for this change.
A separate published case report (PMID:22118009, Liu et al. 2011, J Int Med Res 39:2033-8) describes a de novo STK11 frameshift, c.698_699insG (p.F234LfsX3), in a Chinese child with Peutz-Jeghers syndrome, absent in the clinically unaffected parents and in 50 unrelated controls; that is a different nucleotide change and cannot establish de novo status for c.-1C>T.
Search of the case bundle for 'de novo', 'proband', 'family', 'pedigree', 'parental' and 'meioses' returned no proband or family record; this case is a variant-level assessment with no patient attached.
No STK11 CSPEC/VCEP was found (cspec.found = false; vcep_materials.json reports framework_source = generic_acmg_fallback), so the generic ACMG/AMP 2015 definition of PS2 applies.
Still missing
A documented affected proband carrying NM_000455.5:c.-1C>T
Variant testing in both biological parents
Confirmation of maternity and paternity
Phenotype detail sufficient to apply the relevant STK11/Peutz-Jeghers disease model
PS3Not assessed: no minigene, transcript, or protein functional assay has been reported for STK11 c.-1C>T to evaluate a damaging effect.
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Reasoning
PS3 requires a well-established functional assay demonstrating a damaging effect on the gene or gene product. No functional study of STK11 c.-1C>T exists in the assembled evidence: no minigene splicing assay, no RT-PCR/transcript analysis, no protein or kinase-activity assay, and no mRNA-stability study is reported for this variant in any fetched source. The variant sits at c.-1 in the 5'UTR, immediately 5' of the initiation codon, a position that could plausibly perturb translation initiation or the transcript, but that hypothesis is untested experimentally. Only computational and observational sources are available: SpliceAI in-silico max delta score = 0.01 (a predictor, which belongs to the PP3/BP4 path, not PS3), and a single COSMIC somatic record (COSV114755720, somatic_count = 1), which is a tumor observation, not a functional assay. ClinVar holds conflicting classifications (4 VUS, 3 likely benign, 1 benign, 1-star) but a functional criterion may never be inferred from another source's final classification. With no qualifying functional evidence, PS3 cannot be evaluated and is not assessed; the gap is the absence of any functional assay for this variant.
Evidence considered
No VCEP/ClinGen CSPEC specification exists for STK11 in this case; generic ACMG/AMP 2015 criteria definitions were applied (Richards et al., PMID:25741868).
PubMed/ClinVar literature pass over 8 PMIDs and the 5 fetched full texts found no functional assay performed on STK11 c.-1C>T; the STK11 papers retrieved are cancer-panel case reports, policy gene-list statements, and one laboratory scoring-system methodology paper.
SpliceAI lookup for NM_000455.5:c.-1C>T returned max delta score 0.01 (DS_AG 0.0, DS_AL 0.01, DS_DG 0.001, DS_DL 0.001); this is a computational splice prediction and does not represent a functional assay.
COSMIC record COSV114755720 reports the variant once in a somatic tumour sample; a somatic observation is not a controlled functional assay of gene/protein effect.
ClinVar variation 185127 carries conflicting classifications (4 VUS, 3 likely benign, 1 benign; 1-star, 'criteria provided, conflicting classifications'); classification evidence is not admissible as functional evidence for PS3.
PMID:26467025 (Shearer/Quest laboratory scoring system) discusses how transcript-splicing assays were weighted and notes such assays were generally not counted as functional evidence unless aberrant splicing truncated mRNA in a haploinsufficient model; it reports no STK11 c.-1C>T functional data.
Still missing
No functional assay of any kind (minigene splicing, RT-PCR transcript analysis, protein/kinase-activity, or mRNA stability) has been reported for STK11 c.-1C>T, so a damaging functional effect cannot be established or quantified.
The variant lies at the -1 position of the 5'UTR immediately upstream of the initiation codon; whether it perturbs translation initiation or transcript processing is experimentally untested.
SpliceAI max delta 0.01 and a single COSMIC somatic record are not functional evidence and cannot substitute for PS3.
PM6Not assessed: no affected individual with a presumed de novo c.-1C>T and unconfirmed parental testing is documented.
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Reasoning
PM6 requires an affected individual in whom the variant is presumed de novo but maternity and paternity have not been confirmed (Richards et al. 2015, PMID:25741868). The case contains no affected individual, no proband and no parental information at all: ClinVar VCV000185127 reports only germline submissions with conflicting classifications and no family data, and the literature retrieved names no STK11 c.-1C>T case. Because not even a presumed de novo observation exists, and any PM6 reasoning in STK11 would in any event have to account for the autosomal dominant, age-dependent Penet-Peutz-Jeghers presentation, the criterion cannot be assessed.
Evidence considered
No case report, cohort or registry entry in the case evidence reports NM_000455.5:c.-1C>T in an affected individual; ClinVar VCV000185127 carries only aggregate germline submissions with conflicting classifications and records no clinical observation, family history or segregation data.
PMID:26467025 describes a general rules-based pathogenicity scoring system (16,500 assessments, 11,894 variants, 338 genes, 2010-2014) and provides no STK11- or variant-specific case, parental or segregation data.
PMID:35802134 (ACMG SF v3.1) lists STK11 under Peutz-Jeghers syndrome (OMIM 175200) with autosomal dominant inheritance and 'All P and LP' reporting; it supplies gene-level inheritance context only and mentions no specific STK11 variant.
PMID:22118009 documents a presumed/confirmed de novo STK11 event for a different alteration (c.698_699insG), illustrating that de novo STK11 disease exists in the literature but leaving c.-1C>T itself unevaluated.
Still missing
An affected individual reported to carry NM_000455.5:c.-1C>T
Evidence that the variant was presumed de novo
Details of parental relationship testing where available
Age-at-onset and penetrance context for STK11/Peutz-Jeghers syndrome
PP1Not assessed: zero informative meioses and no variant-carrying affected relatives are documented for c.-1C>T.
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Reasoning
PP1 requires co-segregation of the variant with disease in multiple affected family members (Richards et al. 2015, PMID:25741868). For NM_000455.5:c.-1C>T the case evidence provides no pedigree, no genotype from any affected relative, no genotype from any unaffected relative and therefore zero informative meioses. ClinVar VCV000185127 records only submitter classifications for unrelated germline submitters and contains no family-level data, and none of the retrieved papers reports this nucleotide change (variant_mentioned = false throughout). STK11/Peutz-Jeghers syndrome is autosomal dominant (PMID:35802134), so segregation analysis would be applicable in principle, but with no family data the criterion cannot be assessed.
Evidence considered
The case bundle contains no pedigree, no affected-relative genotype, no unaffected-relative genotype and no meiosis count for NM_000455.5:c.-1C>T.
ClinVar VCV000185127 aggregates eight germline submissions with conflicting classifications (4 uncertain significance, 3 likely benign, 1 benign; no expert panel) but reports no family, co-segregation or meiosis information that could support or refute PP1.
PMID:35802134 establishes autosomal dominant inheritance of STK11-related Peutz-Jeghers syndrome, which is the prerequisite that would make PP1 applicable were family genotypes available; the case-specific record at pvs1_gene_context likewise documents a germline STK11 loss-of-function mechanism for the gene (supporting PMIDs include 22118009, 40860288, 41090222, 42286372, 42696614).
No retrieved paper mentions the c.-1C>T change (PMID:25741868, PMID:26467025, PMID:25980754, PMID:23788249, PMID:35802134 all record variant_mentioned = false), so no published co-segregation series exists for this variant.
Still missing
Affected relatives genotyped for NM_000455.5:c.-1C>T
Unaffected relatives genotyped for the variant
Number of informative meioses
Family pedigree with phenotype confirmation under the STK11/Peutz-Jeghers model
BS3Not assessed: no functional assay reporting normal STK11 c.-1C>T splicing or protein function is available to evaluate BS3.
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Reasoning
BS3 requires a well-established functional assay demonstrating no damaging effect on protein function or splicing. No functional study of STK11 c.-1C>T has been performed in the assembled evidence: no minigene, RT-PCR/transcript, protein, or kinase-activity assay is reported for this variant. The only splicing-relevant data are computational: SpliceAI max delta score = 0.01, which is near the BP4-supporting in-silico range but is a predictor on the PP3/BP4 path, not a functional assay, and cannot be used to meet BS3. The gnomAD frequency data and the conflicting ClinVar classifications are population and classification evidence respectively, not functional evidence. Because no functional assay exists, BS3 cannot be evaluated and is not assessed; the gap is the absence of any functional assay for this variant.
Evidence considered
No VCEP/ClinGen CSPEC specification exists for STK11 in this case; generic ACMG/AMP 2015 criteria definitions were applied (Richards et al., PMID:25741868).
No functional assay performed on STK11 c.-1C>T was identified across the 8 PMIDs screened and the 5 fetched full texts; no source reports normal transcript processing or protein function for this variant.
SpliceAI computational output for NM_000455.5:c.-1C>T (max delta score 0.01; DS_AL 0.01) predicts no significant splice impact, but an in-silico prediction is not the well-established functional assay BS3 requires.
Conflicting ClinVar classifications (variation 185127) and gnomAD low-frequency observations are not functional evidence for BS3.
PMID:26467025 describes how a clinical laboratory weighted transcript-splicing assay evidence but reports no experiment on STK11 c.-1C>T.
Still missing
No functional assay (minigene splicing, RT-PCR transcript analysis, protein/kinase-activity, or mRNA stability) has been reported for STK11 c.-1C>T, so a benign functional effect cannot be established.
SpliceAI max delta 0.01 is computational prediction only and does not satisfy BS3, which requires experimental functional evidence.
BS4Not assessed: no family genotypes are available, so non-segregation of c.-1C>T cannot be demonstrated.
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Reasoning
BS4 requires positive evidence of lack of segregation: the variant present in an affected family member but absent in other affected relatives, interpreted with the gene's penetrance (Richards et al. 2015, PMID:25741868). No family members are genotyped in this case, so there is no non-segregation observation to weigh; the absence of family data is not itself non-segregation evidence and must not be converted into BS4. Submitter classifications in ClinVar VCV000185127 (3 likely benign, 1 benign, 4 uncertain significance) are other groups' conclusions and, per this case's rules, cannot be inferred into a BS4 determination. The criterion therefore cannot be assessed.
Evidence considered
No tested family exists in the case evidence for NM_000455.5:c.-1C>T: no affected relatives, no unaffected relatives, no ages, no phenotype assessments and no non-segregation analysis.
ClinVar VCV000185127 shows conflicting classifications from eight germline submitters (4 uncertain significance, 3 likely benign, 1 benign) with no expert-panel review; these are submitter-level conclusions about the variant, not segregation data, and were not converted into BS4.
PMID:35802134 and the STK11 germline loss-of-function record in pvs1_gene_context establish autosomal dominant Peutz-Jeghers syndrome with age-dependent presentation, the penetrance assumptions under which any BS4 observation would have to be judged.
No retrieved paper mentions c.-1C>T (variant_mentioned = false for PMID:25741868, PMID:26467025, PMID:25980754, PMID:23788249, PMID:35802134), so no published non-segregation observation exists for this variant.
Still missing
Genotypes of affected relatives for NM_000455.5:c.-1C>T
Ages and phenotype status of unaffected variant carriers
Disease penetrance and age-dependent expressivity assumptions for STK11/Peutz-Jeghers syndrome
BP2Not assessed: no second STK11 variant or phasing data exist to establish whether this variant lies in cis or in trans.
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Reasoning
BP2 is met when the variant is observed in cis with a pathogenic variant in any inheritance pattern, or in trans with a pathogenic variant for a fully penetrant dominant gene/disorder (Richards et al. 2015, PMID:25741868). ACMG SF v3.1 (PMID:35802134) establishes that STK11/Peutz-Jeghers syndrome is autosomal dominant, so the trans arm would require a second pathogenic allele on the opposite chromosome, while the cis arm is inheritance-independent. The case supplies only variant-level data (NM_000455.5:c.-1C>T in STK11): there is no proband genotype, no pedigree, no second STK11 variant, and no phasing information. The ClinVar record for variation 185127 was checked and contains only per-submitter classifications, with no cis/trans or phase statement and no co-occurring allele reported. Neither the cis nor the trans arm of BP2 can therefore be evaluated from the available data, so the criterion is left not assessed rather than reported as not met.
Evidence considered
Richards et al. 2015 (PMID:25741868) defines BP2 as observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern.
ACMG SF v3.1 (PMID:35802134) establishes that STK11/Peutz-Jeghers syndrome is autosomal dominant, so the trans arm of BP2 would require a second pathogenic allele on the opposite chromosome.
The ClinVar record for variation 185127 was checked for any phase, cis/trans, or co-occurring-allele statement and contains only per-submitter classifications; no second variant or phasing is reported and no criterion was inferred from any submitter's classification.
No proband genotype, pedigree, or phasing data are present in the case, so neither the cis nor the trans arm of BP2 can be evaluated.
Still missing
Proband genotype, family/pedigree data, and phase information are absent; a second STK11 variant with known phase would be required to evaluate either the cis or the trans arm of BP2.
Not applicable · 10· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: c.-1C>T is a 5' UTR base upstream of the initiation codon, not a null type, and SpliceAI max delta 0.01 excludes a splice-null effect.
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Reasoning
PVS1 (Richards et al. 2015, PMID:25741868; ClinGen SVI PVS1 framework, Abou Tayoun et al. 2018, PMC6185798) applies only to predicted-null variants: nonsense, frameshift, canonical +/-1 or 2 splice-site, initiation-codon, or single/multi-exon deletion variants. NM_000455.5:c.-1C>T (STK11, MANE Select) is a single-nucleotide substitution at c.-1, which Mutalyzer/VariantValidator normalize as lying outside the CDS and upstream of it (outside_cds = upstream), i.e. a 5' UTR base immediately 5' of the initiation codon. The initiation codon itself (c.1-c.3, ATG) is unchanged, so this is not an initiation-codon variant, and it is not a nonsense or frameshift allele. In the MANE transcript NM_000455.5 the position sits deep inside exon 1 (exon 1 spans c.-1136 to c.290), roughly 291 bp from the nearest exon/intron boundary (the exon 1 donor at c.290/c.291), so it is not a canonical +/-1 or 2 splice site; SpliceAI independently predicts no splice effect (max delta 0.01; DS_AG 0.0, DS_AL 0.01, DS_DG 0.001, DS_DL 0.001), excluding a de facto splice-null. STK11 haploinsufficiency is the established germline mechanism for Peutz-Jeghers syndrome, so the gene-level precondition for PVS1 (loss of function is a disease mechanism) is satisfied, but the variant belongs to no PVS1-eligible null class. PVS1 is therefore not applicable and is not met at any strength; because the criterion is not met, no SVI/VCEP downgrade rule is invoked and the strength field is left null rather than a tier word.
Variant normalization (Mutalyzer/VariantValidator, via prefetch): NM_000455.5:c.-1C>T normalizes unchanged to NM_000455.5:c.-1C>T with location type point and outside_cds = upstream, and VariantValidator reports variant_exonic_positions start_exon = end_exon = 1; the change is therefore a 5' UTR substitution immediately 5' of the initiation codon, not a coding change.
Transcript structure (NM_000455.5, MANE Select, refseq_select true; 5' UTR 1136 nt, CDS c.1-c.1302 = 434 aa, 3' UTR 855 nt): exon 1 spans c.-1136 to c.290, so position c.-1 lies well inside exon 1 and ~291 bp from the exon 1 donor site (c.290/c.291); it is not a canonical +/-1 or 2 splice-consensus position.
SpliceAI lookup for NM_000455.5:c.-1C>T (hg37; b=basic, distance 500) returned max delta score 0.01 with all component deltas <=0.01 (DS_AG 0.0, DS_AL 0.01, DS_DG 0.001, DS_DL 0.001); Pangolin SG 0.002 / SL -0.008; no splice-altering effect is predicted, so the variant is not functioning as a splice-null.
Gene-level PVS1 precondition (pvs1_gene_context): STK11 germline loss of function is an established disease mechanism (haploinsufficiency causes Peutz-Jeghers syndrome), pvs1_gene_gate = eligible, so generic PVS1 assessment was warranted for the gene; this gate is about the gene, not this variant.
Governing specification: no ClinGen CSPEC and no VCEP/gene-specific framework is available for STK11 (vcep_materials.json found=false; framework_mode = generic_acmg), so the generic ACMG/AMP 2015 framework (PMID:25741868) plus the ClinGen SVI PVS1 recommendations (PMC6185798) apply; neither treats a 5' UTR substitution as a PVS1-eligible null class.
The ClinVar record for this variant is conflicting (4 VUS, 3 likely benign, 1 benign; no expert-panel submission) and was not used to infer, or to support, any PVS1 determination.
No PVS1 strength tier word was written because the criterion is not met; if it had been met un-downgraded at full strength the correct literal value would have been the tier word 'very strong', and any downgrade to strong/moderate/supporting would have required a named SVI/VCEP rule (e.g. NMD escape or non-critical-exon location), none of which is applicable to a 5' UTR substitution.
PS1N/APS1 (Richards et al. 2015, PMID:25741868) requires the same amino acid change as a previously established pathogenic variant, evaluated regardless of the underlying nucleotide change. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, no altered amino acid exists at this position to compare against any previously established pathogenic missense variant, so PS1'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.
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Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: canonical_splice (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM1N/APM1 (Richards et al. 2015, PMID:25741868) applies to a missense variant located in a mutational hot spot and/or a critical, well-established functional domain without benign variation. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, no altered residue exists to evaluate for mutational hot-spot or critical-domain membership, so PM1'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.
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Rule
deterministic_prefilter: requires_missense
Evidence considered
Deterministic consequence classification: canonical_splice (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PM3N/ANot applicable: PM3 is restricted to recessive disorders, and STK11-related Peutz-Jeghers syndrome is an autosomal dominant condition.
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Reasoning
PM3 is defined for recessive disorders ("For recessive disorders, detected in trans with a pathogenic variant"; Richards et al. 2015, PMID:25741868). STK11-related Peutz-Jeghers syndrome is an autosomal dominant disorder: the ACMG SF v3.1 gene list records the STK11/PJS row as AD in Table 1 (PMID:35802134), the NCBI Gene entry describes autosomal dominant Peutz-Jeghers syndrome, and no source in the collected evidence documents a recessive STK11 disease mechanism. Because the disorder is dominant, the in-trans-with-a-pathogenic-variant logic that PM3 encodes cannot be satisfied regardless of phase. Independently, the case input is a single variant (NM_000455.5:c.-1C>T) with no second STK11 allele and no phase or pedigree data, so no in-trans observation exists to evaluate. PM3 is therefore not applicable to this variant.
Evidence considered
Richards et al. 2015 (PMID:25741868) defines PM3 as "For recessive disorders, detected in trans with a pathogenic variant", restricting the criterion to autosomal recessive disease.
Peutz-Jeghers syndrome, the STK11-related disorder, is autosomal dominant: ACMG SF v3.1 (PMID:35802134) lists the STK11/PJS row as AD in Table 1, and no source in this case documents a recessive STK11 mechanism.
The case input is a single variant (NM_000455.5:c.-1C>T) with no second STK11 variant and no phase or pedigree data, so no in-trans observation exists to evaluate.
Still missing
No recessive STK11 disease mechanism is documented anywhere in the collected evidence; PM3 would only become applicable if a recessive mode of inheritance were established for STK11.
PM4N/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.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. 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.
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PM5N/APM5 (Richards et al. 2015, PMID:25741868) requires a novel missense change at an amino acid residue where a different missense change has previously been determined to be pathogenic. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, no missense change exists at this residue to compare against a different pathogenic missense change at the same position, so PM5'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_missense
Evidence considered
Deterministic consequence classification: canonical_splice (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
PP2N/APP2 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene with a low rate of benign missense variation, where missense variants are a common mechanism of disease. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, the gene's missense-constraint properties are irrelevant because no missense change is present to evaluate, so PP2'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_missense
Evidence considered
Deterministic consequence classification: canonical_splice (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP1N/ABP1 (Richards et al. 2015, PMID:25741868) applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. NM_000455.5:c.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. As a result, the gene's truncating-variant mechanism is irrelevant because no missense change is present to evaluate, so BP1'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_missense
Evidence considered
Deterministic consequence classification: canonical_splice (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
BP3N/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.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. 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.
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BP7N/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.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. 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.
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Rule
deterministic_prefilter: requires_synonymous
Evidence considered
Deterministic consequence classification: canonical_splice (prefetch.json normalized protein consequence)
Sources
generic_acmg_combination_rules
Identifiers
Gene
STK11
Transcript
NM_000455.5
Coding (HGVS c.)
NM_000455.5:c.-1C>T
Protein (HGVS p.)
NP_000446.1:p.?
GRCh38
chr19:1206913 C>T
GRCh37
chr19:1206912 C>T
Location and type
Exon 1 · canonical splice
ClinVar
185127
COSMIC
COSV114755720
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
—
Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in STK11—Select a row to find it on the plot; use the link to open its page.
AF 2.1e-05 · 33 / 1,575,088 alleles · 0 hom · FAF 1.6e-05
Remaining individuals7 / 61,048
0.00011
European (non-Finnish)26 / 1,161,034
2.2e-05
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.1e-05 · 2 / 187,514 alleles · 0 hom · FAF 4.1e-06
European (non-Finnish)2 / 80,304
2.5e-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= 2.09512e-05; MAF= 0.00210%, 33/1575088 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000114664; MAF= 0.01147%, 7/61048 alleles, homozygotes = 0); grpmax FAF= 1.558e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.06659e-05; MAF= 0.00107%, 2/187514 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.49054e-05; MAF= 0.00249%, 2/80304 alleles, homozygotes = 0); grpmax FAF= 4.13e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -80 bp
0.010
SpliceAI acceptor gainat -289 bp
0.000
SpliceAI donor lossat +57 bp
0.001
SpliceAI donor gainat -487 bp
0.001
Pangolin splice lossmagnitude shown
-0.008
Pangolin splice gain
0.002
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
BP4SupportingMet (supporting): SpliceAI max delta 0.01 versus the <=0.1 BP4 supporting threshold.
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Reasoning
Same scope decision as PP3: NM_000455.5:c.-1C>T is a splice-region variant (consequence class canonical_splice; non-missense, non-synonymous), so BP4 is evaluated on the SpliceAI path only. SpliceAI max delta score is 0.01 (DS_AG 0.0, DS_AL 0.01, DS_DG 0.001, DS_DL 0.001), at or below the <=0.1 BP4 supporting cutoff (Jaganathan et al. 2019, Cell; PMID:30661751), so computational evidence predicts no impact on splicing and BP4 is met at supporting strength. No stronger BP4 tier is supported by this score, and the missense path is not a fallback: REVEL and BayesDel were not available and BP4 is not derived from them. No STK11 VCEP/CSPEC specification exists (ClinGen CSPEC not found; framework_mode generic_acmg), so the generic threshold applies. The single SpliceAI prediction is not double-counted across PP3/BP4/BP7.
Rule
BP4_spliceai_max_delta<=0.1
Evidence considered
SpliceAI lookup for NM_000455.5:c.-1C>T (hg37) returned max delta score 0.01, at or below the <=0.1 BP4 supporting cutoff (Jaganathan et al. 2019, Cell; PMID:30661751).
BP4 taken from the SpliceAI (splice) path only, matched to the variant's canonical_splice consequence class; no evidence was drawn from the REVEL/BayesDel missense path.
No ClinGen CSPEC or VCEP/gene-specific PP3/BP4 lookup specification exists for STK11 (vcep_materials.json found=false; framework_mode generic_acmg), so no pre-assigned VCEP code overrides the generic cutoff.
The same SpliceAI prediction is not reused to satisfy PP3, BP7, or any other criterion.
PP3Not met: SpliceAI max delta 0.01, far below the >=0.2 supporting PP3 threshold.
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Reasoning
NM_000455.5:c.-1C>T is a splice-region variant in STK11 (consequence class canonical_splice; a non-missense, non-synonymous substitution one base upstream of the initiation codon, predicted protein NP_000446.1:p.?), so PP3 takes computational evidence from the SpliceAI path only, never from REVEL/BayesDel. SpliceAI max delta score is 0.01 (DS_AG 0.0, DS_AL 0.01, DS_DG 0.001, DS_DL 0.001), below both the >=0.2 supporting and >=0.5 moderate PP3 cutoffs (Jaganathan et al. 2019, Cell; PMID:30661751), so no splice-altering effect is predicted and PP3 is not met. No STK11 VCEP/CSPEC specification exists (ClinGen CSPEC not found; framework_mode generic_acmg), so the generic SpliceAI thresholds apply. REVEL and BayesDel were not available (both null/not found) and would not be applicable to a non-missense variant in any case.
Rule
PP3_spliceai_max_delta>=0.2
Evidence considered
SpliceAI lookup for NM_000455.5:c.-1C>T (hg37) returned max delta score 0.01 with all component deltas <=0.01 (DS_AG 0.0, DS_AL 0.01, DS_DG 0.001, DS_DL 0.001); Pangolin SG 0.002 / SL -0.008.
Path selection: the variant's own consequence class is canonical_splice (splice-region; non-missense, non-synonymous), so only the SpliceAI path contributes to PP3/BP4; the REVEL/BayesDel (missense) path is inapplicable.
Governing specification: no ClinGen CSPEC and no VCEP/gene-specific framework is available for STK11 (vcep_materials.json found=false, framework_mode generic_acmg), so the generic ACMG/AMP 2015 framework and the published SpliceAI cutoffs (Jaganathan et al. 2019, PMID:30661751) apply.
REVEL and BayesDel were queried and were not found (score null), so the missense calibration could not be and need not be applied.
No double-counting: the same SpliceAI prediction is not reused to support PVS1 or any other criterion.
BP7N/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.-1C>T in STK11 is a variant at a canonical ±1/2 splice-consensus position predicted to produce NP_000446.1:p.?. 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.
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Rule
deterministic_prefilter: requires_synonymous
Evidence considered
Deterministic consequence classification: canonical_splice (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).
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.
The ACMG/AMP joint consensus standards and guidelines for the interpretation of sequence variants (Richards et al. 2015). It is the general framework document that defines PVS1 and lists the variant types that can be assumed to be null (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single- or multi-exon deletion), while cautioning that such variants should be classified as pathogenic only when null variants are an established mechanism consistent with the gene's inheritance pattern. It is not a variant- or gene-specific study and does not mention STK11 or c.-1C>T. It confirms the PVS1 eligibility categories used here and shows that a 5' UTR substitution is not among them.
→ PM2 · supporting→ BP4 · supportingDoes not name this variant
Certain types of variants (e.g., nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single exon or multiexon deletion) can often be assumed to disrupt gene function by leading to a complete absence of the gene product by lack of transcription or nonsense-mediated decay of an altered transcript.
Location PROPOSED CRITERIA FOR INTERPRETATION OF SEQUENCE VARIANTS, subsection "PVS1 null variants" (paragraph 1); see also Table 3 (pathogenic criteria, PVS1).
Context Consensus guideline document (American College of Medical Genetics and Genomics / Association for Molecular Pathology); no cohort or assay.
Other recorded publications
A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.
A standardized, rules-based weighted scoring system used at a CLIA-certified laboratory to assess pathogenicity of sequence variants (16,500 assessments on 11,894 distinct variants across 338 genes, 2010-2014). STK11 is not named in the main text and no data for c.-1C>T are reported. Relevant general methodology: null variants defined as frameshift, nonsense, or canonical splice-site variants at the +/-1,2 positions associated with out-of-frame events were assigned +2 points; intronic variants outside the canonical splice site were evaluated for their effect on splicing. This supports treating only canonical +/-1,2 changes (and comparable truncating types) as null, which c.-1C>T is not.
A special consideration was given to genes where null variants (e.g., frameshift, nonsense, canonical splice site variants at the +/-1,2 positions associated with out-of-frame events) were documented in the literature to cause well-characterized disease phenotypes. These variants were assigned +2 points which raised their score to 6 (likely pathogenic)
Materials and Methods, 'A Rules-Based, Weighted Variant Scoring System'
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
Green RC et al. · 2013
ACMG Working Group policy statement on incidental (secondary) findings in clinical exome/genome sequencing; not an experimental study and reports no cohort, assay, segregation or frequency data. The variant c.-1C>T is not mentioned and the STK11 gene itself is not named in the supplied text (genes appear in a Table not included). Its relevant content is the reporting framework for previously reported pathogenic variants or previously unreported variants of a type expected to cause the disorder, a general statement that carries no variant- or phenotype-specific evidence for this case.
For most genes, only variants that have been previously reported and are a recognized cause of the disorder or variants that are previously unreported but are of the type which is expected to cause the disorder, as defined by prior ACMG guidelines, should be reported.
RECOMMENDATIONS, paragraph 6 (see also Discussion, paragraph 3)
Identification of a Variety of Mutations in Cancer Predisposition Genes in Patients With Suspected Lynch Syndrome.
Yurgelun MB et al. · 2015
Multigene panel testing (25 cancer susceptibility genes including STK11) in 1260 individuals undergoing clinical Lynch syndrome testing; STK11 was classified as a high-penetrance cancer susceptibility gene. One subject carried a pathogenic STK11 mutation together with a pathogenic MSH6 mutation and had colorectal, endometrial and breast cancer. No nucleotide-level or protein-level detail of the STK11 alteration is given and STK11 c.-1C>T is not named, so no de novo, parental or segregation observation for this variant can be taken from the paper.
One had both pathogenic STK11 and MSH6 mutations, with a personal history of CRC, EC, and breast cancer.
Results, Germline Findings (paragraph beginning 'Nine individuals were found to carry mutations in high-penetrance non-LS cancer susceptibility genes other than BRCA1/2')
Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi
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.
ACMG SF v3.1 list for reporting of secondary findings in clinical exome and genome sequencing: A policy statement of the American College of Medical Genetics and Genomics (ACMG).
The ACMG SF v3.1 policy statement (consensus gene-list recommendation), not a variant study. It lists STK11 in Table 1 under genes related to cancer phenotypes, associating it with Peutz-Jeghers syndrome (OMIM 175200), autosomal dominant inheritance, and recommending that all pathogenic and likely pathogenic variants be reported as secondary findings. This supplies the gene-level inheritance context (autosomal dominant) under which segregation or de novo evidence would be evaluated, but contains no cohort, family, segregation or frequency data for STK11 and does not name c.-1C>T.
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= 2.09512e-05; MAF= 0.00210%, 33/1575088 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000114664; MAF= 0.01147%, 7/61048 alleles, homozygotes = 0); grpmax FAF= 1.558e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.06659e-05; MAF= 0.00107%, 2/187514 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.49054e-05; MAF= 0.00249%, 2/80304 alleles, homozygotes = 0); grpmax FAF= 4.13e-06.
gnomAD-Canada
Not available in gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (3 clinical laboratories) and as Benign (1 clinical laboratory). (ClinVarID = 185127)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
Somatic
This variant has previously been reported in somatic cancers (COSMIC; COSV114755720, n = 1 times).
This variant was interpreted by pipeline 8.0.0.
The current version is 11.0.07.
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