Variant classification summary

NM_000455.5:c.160C>T

STK11 · NP_000446.1:p.(Leu54=) · NM_000455.5

GRCh37: chr19:1207072 C>T · GRCh38: chr19:1207073 C>T

Gene: STK11 Transcript: NM_000455.5

Final call

VUS

PM2 supporting BP7 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.(Leu54=)

gnomAD AF

4.337244288468879e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

VUS: PM2 (supporting) - gnomAD v4.1 AF 4.34e-06 and v2.1 AF 8.05e-06 fall below the 0.01% rarity ceiling, establishing rarity only.

2

VUS: BP7 (supporting) - synonymous p.(Leu54=) with SpliceAI maximum delta 0.003, far below the 0.1 no-splice-impact cutoff.

3

VUS: one supporting pathogenic plus one supporting benign criterion reaches no ACMG/AMP 2015 combination threshold.

Final determination: Under the generic ACMG/AMP 2015 fallback, 1 supporting pathogenic (PM2) plus 1 supporting benign (BP7) criterion satisfies no Pathogenic, Likely Pathogenic, Benign or Likely Benign combination, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_000455.5:c.160C>T in STK11 is a synonymous (silent) substitution predicted to produce NP_000446.1:p.(Leu54=). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1'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.	pvs1_generic_framework generic_acmg_combination_rules
PS1	N/A	PS1 (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.160C>T in STK11 is a synonymous (silent) substitution predicted to produce NP_000446.1:p.(Leu54=). 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.	generic_acmg_combination_rules
PS2	Not assessed	Not assessed: no proband or confirmed-parentage (trio) genotype data exists for STK11 c.160C>T, so a de novo occurrence cannot be evaluated.	PMID:25741868 clinvar
PS3	Not met	Not met: no functional assay reports STK11 c.160C>T (p.Leu54=), and the only molecular data are computational SpliceAI 0.00, not an assay.	PMID:25741868 generic_acmg_combination_rules final_classification_framework
PS4	Not met	Not met: no case-control or case-series enrichment data exists for this synonymous variant, so no odds ratio was available for any threshold comparison.	clinvar PMID:25741868 PMID:26389258 PMID:26389505 PMID:27854360
PM1	N/A	PM1 (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.160C>T in STK11 is a synonymous (silent) substitution predicted to produce NP_000446.1:p.(Leu54=). 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.	generic_acmg_combination_rules
PM2	Met	Met (supporting): gnomAD v4.1 AF 4.34e-06 and v2.1 AF 8.05e-06 are below the 0.0001 PM2 threshold, with zero homozygotes.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: STK11/Peutz-Jeghers syndrome is autosomal dominant (PMID:27854360), so PM3's requirement for a recessive-disorder variant in trans with a pathogenic allele cannot be satisfied.	generic_acmg_combination_rules PMID:25741868 PMID:27854360 clinvar
PM4	N/A	PM4 (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.160C>T in STK11 is a synonymous (silent) substitution predicted to produce NP_000446.1:p.(Leu54=). 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.	pvs1_generic_framework generic_acmg_combination_rules
PM5	N/A	PM5 (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.160C>T in STK11 is a synonymous (silent) substitution predicted to produce NP_000446.1:p.(Leu54=). 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.	generic_acmg_combination_rules
PM6	Not assessed	Not assessed: no proband or parental testing data exists for STK11 c.160C>T, so an assumed de novo occurrence cannot be evaluated.	PMID:25741868 clinvar
PP1	Not assessed	Not assessed: no pedigree or genotyped affected relatives exist, so co-segregation meioses for STK11 c.160C>T cannot be counted.	PMID:25741868 clinvar
PP2	N/A	PP2 (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.160C>T in STK11 is a synonymous (silent) substitution predicted to produce NP_000446.1:p.(Leu54=). 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.	generic_acmg_combination_rules
PP3	N/A	Not applicable: this synonymous, non-splice-region variant falls outside PP3's calibrated missense-REVEL and splice-region-SpliceAI paths.	PMID:25741868 final_classification_framework
PP4	Not met	Not met: no affected individual carrying this variant is reported, so no case-level Peutz-Jeghers-specific phenotype can be matched to the genotype.	clinvar PMID:25741868 PMID:27854360 PMID:31672839 PMID:25645574
PP5	Not met	Not met: the exact-variant ClinVar record is a 2-star Benign/Likely benign aggregate from five clinical laboratories, with zero expert-panel submissions.	clinvar PMID:25741868
BA1	Not met	Not met: highest observed gnomAD subpopulation AF 0.00267% (v4.1 AFR) is far below the 5% BA1 stand-alone threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: highest observed gnomAD subpopulation AF 0.00267% (v4.1 AFR) is roughly 375-fold below the 1% BS1 threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not met	Not met: zero homozygotes and only 7 heterozygous alleles observed, and Peutz-Jeghers syndrome penetrance is not full at an early age.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: no functional assay of STK11 c.160C>T (p.Leu54=) exists, so preserved function/normal splicing cannot be demonstrated.	PMID:25741868 generic_acmg_combination_rules final_classification_framework
BS4	Not assessed	Not assessed: no family or segregation data exists, so non-segregation in affected relatives cannot be shown for STK11 c.160C>T.	PMID:25741868 clinvar
BP1	N/A	BP1 (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.160C>T in STK11 is a synonymous (silent) substitution predicted to produce NP_000446.1:p.(Leu54=). 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.	generic_acmg_combination_rules
BP2	Not met	Not met: no source documents c.160C>T in cis or trans with a pathogenic allele - all five ClinVar submissions report the variant in isolation without phase information.	generic_acmg_combination_rules PMID:25741868 clinvar PMID:25645574 PMID:31672839 PMID:27854360
BP3	N/A	BP3 (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.160C>T in STK11 is a synonymous (silent) substitution predicted to produce NP_000446.1:p.(Leu54=). 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.	pvs1_generic_framework generic_acmg_combination_rules
BP4	N/A	Not applicable: BP4's missense and splice-region paths do not cover this synonymous variant, whose SpliceAI 0.003 no-impact result is credited to BP7.	PMID:25741868 final_classification_framework
BP5	Not met	Not met: no affected individual carrying this variant with a documented alternate molecular basis for disease has been reported in any consulted source.	clinvar PMID:25741868 PMID:26389258 PMID:26389505
BP6	Not met	Not met: the exact-variant ClinVar Benign/Likely benign label comes only from five clinical laboratories, with no expert-panel assertion to trigger BP6.	clinvar PMID:25741868
BP7	Met	Met at supporting strength: synonymous p.(Leu54=) with SpliceAI max delta 0.003, far below the 0.1 no-splice-impact cutoff.	spliceai PMID:25741868 final_classification_framework

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