Variant classification summary

NM_000455.4:c.658C>T

STK11 · NP_000446.1:p.(Gln220Ter) · NM_000455.4

GRCh37: chr19:1220640 C>T · GRCh38: chr19:1220641 C>T

Gene: STK11 Transcript: NM_000455.4

Final call

Pathogenic

PVS1 very strong PM2 supporting PP4 supporting

Variant details

Gene

STK11

Transcript

NM_000455.4

Protein

NP_000446.1:p.(Gln220Ter)

gnomAD AF

0.0 (v4.1)

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PVS1 very strong: c.658C>T creates p.Gln220Ter in exon 5 of 9 and truncates STK11 well before its terminal exon.

2

PM2 supporting: the variant is absent from evaluated population datasets, with gnomAD v4.1 frequency 0.

3

PP4 supporting: the exact variant was reported in a child with Peutz-Jeghers syndrome and buccal freckling.

Final determination: Under the generic ACMG/AMP 2015 fallback, one very strong pathogenic criterion plus two supporting pathogenic criteria leads to a Pathogenic classification.

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	Met	Met, very strong: c.658C>T creates p.Gln220Ter in exon 5 of 9, far upstream of the terminal junction and truncating the 434-residue STK11 protein.	pvs1_generic_framework PMID:17026623 PMID:9887330
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_000455.4:c.658C>T in STK11 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000446.1:p.(Gln220Ter). 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: the variant is reported in a proband, but parental testing and confirmed absence in both parents are not reported.	PMID:17026623 PMID:9887330 generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no variant-specific functional assay was reported for c.658C>T; the cited study tested other LKB1 alleles.	PMID:9887330
PS4	Not assessed	Not assessed: exact-variant reports document individual Peutz–Jeghers cases but provide no case-control enrichment statistic or comparison with controls.	PMID:17026623 PMID:9887330
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_000455.4:c.658C>T in STK11 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000446.1:p.(Gln220Ter). 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 at supporting strength: the variant was absent from gnomAD v2.1 and non-cancer subsets, and gnomAD v4.1 showed AF 0 (0/1,608,534).	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: STK11-associated Peutz-Jeghers syndrome is autosomal dominant, so recessive biallelic-in-trans evidence does not apply.	PMID:17026623 PMID:9887330
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_000455.4:c.658C>T in STK11 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000446.1:p.(Gln220Ter). 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_000455.4:c.658C>T in STK11 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000446.1:p.(Gln220Ter). 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: affected-patient reports lack sufficient family and parental information to support presumed de novo occurrence.	PMID:17026623 PMID:9887330 generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no informative relatives with documented genotype and phenotype are reported for evaluating co-segregation.	PMID:17026623 PMID:9887330 PMID:9850045 generic_acmg_combination_rules
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_000455.4:c.658C>T in STK11 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000446.1:p.(Gln220Ter). 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: NM_000455.4:c.658C>T is a nonsense variant producing p.(Gln220Ter), outside PP3's missense or splice-region scope.
PP4	Met	Met (supporting): the exact variant was reported in a child with Peutz–Jeghers syndrome and buccal freckling, a characteristic STK11-associated phenotype.	PMID:17026623 PMID:9887330
PP5	N/A	Not applicable: ClinVar shows a single-submitter Pathogenic record, but no exact-variant expert-panel Pathogenic or Likely pathogenic classification.	clinvar
BA1	Not met	Not met: gnomAD v4.1 allele frequency was 0 (0/1,608,534), far below the BA1 threshold of >=0.05.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v4.1 allele frequency was 0 (0/1,608,534), below the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not met	Not met: no healthy-adult observation was documented, with 0 alternate alleles and 0 homozygotes in gnomAD v4.1.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no controlled assay demonstrated preserved STK11 function for p.Gln220Ter, and available functional tests used other alleles.	PMID:9887330
BS4	Not assessed	Not assessed: no informative unaffected relatives with documented carrier status are available to demonstrate non-segregation.	PMID:17026623 PMID:9887330 generic_acmg_combination_rules
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_000455.4:c.658C>T in STK11 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000446.1:p.(Gln220Ter). 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 assessed	Not assessed: no additional pathogenic variant or cis/trans phase information is documented for the c.658C>T proband.	PMID:17026623 PMID:9887330
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_000455.4:c.658C>T in STK11 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000446.1:p.(Gln220Ter). 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: NM_000455.4:c.658C>T is a nonsense variant producing p.(Gln220Ter), outside BP4's missense or splice-region scope.
BP5	Not assessed	Not assessed: no alternate molecular etiology or BP5-specific benign likelihood-ratio result is documented for the exact variant.	PMID:17026623 PMID:9887330
BP6	N/A	Not applicable: ClinVar has no exact-variant expert-panel Benign or Likely benign classification, and the available record is a single-submitter Pathogenic assertion.	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_000455.4:c.658C>T in STK11 is a nonsense substitution introducing a premature stop codon predicted to produce NP_000446.1:p.(Gln220Ter). 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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