Variant classification summary

NM_000455.5:c.911G>A

STK11 · NP_000446.1:p.(Arg304Gln) · NM_000455.5

GRCh37: chr19:1221996 G>A · GRCh38: chr19:1221997 G>A

Gene: STK11 Transcript: NM_000455.5

Final call

VUS

PM2 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.(Arg304Gln)

gnomAD AF

1.8462517905459174e-05 (v4.1)

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: gnomAD v4.1 allele frequency is below 0.0001 with zero homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, one supporting criterion alone does not satisfy any pathogenic, likely pathogenic, likely benign, or benign combination, so the final call is VUS.

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.911G>A in STK11 is a missense substitution predicted to produce NP_000446.1:p.(Arg304Gln). 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	Not assessed	PS1 could not be assessed because its agent did not produce valid output.
PS2	Not assessed	Not assessed: no parental testing or confirmed de novo observation is documented for the present c.911G>A (p.Arg304Gln) variant.
PS3	Not assessed	Not assessed: no validated functional assay tested the exact R304Q variant, while available assays studied different STK11 substitutions such as R304W.	PMID:12552571 PMID:17404884 PMID:9837816
PS4	Not assessed	Not assessed: no exact-variant case-control counts, enrichment statistic, odds ratio, or affected-case versus control comparison is available.	clinvar
PM1	Not assessed	PM1 could not be assessed because its agent did not produce valid output.
PM2	Met	Met at supporting: gnomAD v4.1 all-comers AF 1.84625e-05 is below the generic PM2 threshold of 0.0001, with zero homozygotes.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: STK11-associated Peutz–Jeghers syndrome is autosomal dominant, so recessive biallelic evidence criterion PM3 does not apply.	PMID:17404884 PMID:25741868
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.911G>A in STK11 is a missense substitution predicted to produce NP_000446.1:p.(Arg304Gln). 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	Not assessed	PM5 could not be assessed because its agent did not produce valid output.
PM6	Not assessed	Not assessed: no apparently de novo occurrence is reported for c.911G>A (p.Arg304Gln), and parental testing is unavailable.
PP1	Not assessed	Not assessed: zero informative meioses or affected relatives carrying c.911G>A (p.Arg304Gln) are documented.
PP2	Not assessed	PP2 could not be assessed because its agent did not produce valid output.
PP3	Not met	Not met: REVEL 0.567 is below the supporting PP3 threshold of 0.644 for missense variants.	revel
PP4	Not assessed	Not assessed: no patient phenotype or phenotype-specific diagnostic findings are documented for comparison with an STK11-related disorder.	clinvar
PP5	Not met	Not met: the exact ClinVar record has zero expert-panel submissions and no expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: all-comers gnomAD v4.1 AF 1.84625e-05 is far below the generic BA1 threshold of 0.05.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the highest observed gnomAD ancestry-specific AF, 0.000183666, remains below the generic BS1 threshold of 0.01.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	Not met	Not met: gnomAD v2.1 and v4.1 each report 0 homozygotes, so no healthy-homozygote evidence supports BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no validated benign functional assay tested exact STK11 R304Q with evidence of preserved biologically relevant function.	PMID:12552571 PMID:17404884 PMID:9837816
BS4	Not assessed	Not assessed: no tested unaffected relatives or phenotype-informed non-segregation observations are documented for c.911G>A (p.Arg304Gln).
BP1	Not assessed	BP1 could not be assessed because its agent did not produce valid output.
BP2	Not assessed	Not assessed: no documented cis/trans phase or co-occurrence observation with a pathogenic STK11 variant is available.	PMID:25741868 clinvar
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.911G>A in STK11 is a missense substitution predicted to produce NP_000446.1:p.(Arg304Gln). 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	Not met	Not met: REVEL 0.567 exceeds the supporting BP4 threshold of 0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: no affected individual with a documented alternate molecular diagnosis is available to support BP5.	clinvar
BP6	Not met	Not met: one ordinary laboratory submission is Likely benign, but the exact ClinVar record has zero expert-panel submissions.	clinvar
BP7	N/A	BP7 (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.911G>A in STK11 is a missense substitution predicted to produce NP_000446.1:p.(Arg304Gln). 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.	generic_acmg_combination_rules

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