Variant classification summary

NM_000455.5:c.249G>A

STK11 · NP_000446.1:p.(Lys83=) · NM_000455.5

GRCh37: chr19:1207161 G>A · GRCh38: chr19:1207162 G>A

Gene: STK11 Transcript: NM_000455.5

Final call

Likely Benign

PM2 supporting BP4 supporting BP6 supporting BP7 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.(Lys83=)

gnomAD AF

3.722888067647358e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

NM_000455.5:c.249G>A (p.Lys83=) is a synonymous variant in STK11 with no predicted effect on splicing (SpliceAI max delta=0.00).

2

The variant is present at extremely low frequency in gnomAD (v2.1: 2/272,834 alleles, AF=0.00073%; v4.1: 6/1,611,652 alleles, AF=0.00037%), satisfying PM2 at supporting level.

3

ClinVar consensus from 5 clinical laboratories classifies this variant as Likely benign/Benign (ClinVar ID 486990), supporting BP6 at supporting strength.

4

As a synonymous variant with no predicted splice impact, BP7 applies at supporting strength.

5

Computational evidence shows no deleterious effect, satisfying BP4 at supporting strength.

6

No functional studies, case-control data, segregation data, or de novo reports were identified for this variant. PP5 is not met as ClinVar reports a benign classification. PS3, PS4, and PP3 are not met.

7

PVS1, PS1, PM1, PM5, PP2, and BP1 are not applicable as the variant is synonymous with no amino acid change. BA1, BS1 thresholds are not met due to extremely low population frequency.

8

Overall, the evidence profile shows 1 supporting pathogenic criterion (PM2) versus 3 supporting benign criteria (BP4, BP6, BP7). The net classification is Likely benign by ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Benign classification because either one strong benign criterion plus one supporting benign criterion, or at least two supporting benign criteria, are present.

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	NM_000455.5:c.249G>A is a synonymous variant (p.Lys83=) with SpliceAI max delta score of 0.00. It does not fall into the PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The generic PVS1 framework is not applicable.	pvs1_variant_assessment spliceai
PS1	N/A	This is a synonymous variant (p.Lys83=) with no amino acid change. PS1 requires the same amino acid change as a previously established pathogenic variant; there is no amino acid change to compare.
PS2	Not assessed	No de novo data are available for this variant. No publications or case records document a confirmed de novo occurrence of NM_000455.5:c.249G>A.
PS3	Not met	No functional studies were identified for NM_000455.5:c.249G>A (p.Lys83=). The variant is synonymous and has not been characterized in any experimental assay. OncoKB lists Unknown Oncogenic Effect with no supporting PMIDs. Domain-level inference does not satisfy PS3's functional evidence requirement.	oncokb
PS4	Not assessed	No case-control or cohort data are available to assess variant prevalence in affected individuals versus controls. The publications associated with this variant through ClinVar are clinical guidelines and policy statements, not variant-specific observational studies.
PS5	N/A	No evidence of a founder effect for NM_000455.5:c.249G>A. This criterion is reserved for variants with established founder mutation status in specific populations.
PM1	N/A	NM_000455.5:c.249G>A is a synonymous variant (p.Lys83=) and does not alter the amino acid sequence. PM1 applies to variants that disrupt a critical functional domain at the protein level; a synonymous variant with no splice effect does not meet this criterion regardless of domain location.	spliceai
PM2	Met	NM_000455.5:c.249G>A is present at extremely low frequency in gnomAD v2.1 (AF=0.00073%, 2/272,834 alleles, 0 homozygotes) and gnomAD v4.1 (AF=0.00037%, 6/1,611,652 alleles, grpmax FAF=7.9e-7). This is well below the 0.1% threshold for PM2.	gnomad_v2 gnomad_v4
PM5	N/A	NM_000455.5:c.249G>A is a synonymous variant producing no amino acid change (p.Lys83=). PM5 requires a different pathogenic missense change at the same residue; there is no amino acid substitution at this position to compare.
PM6	Not assessed	No confirmed de novo occurrence of NM_000455.5:c.249G>A has been reported in the literature or ClinVar submissions. PM6 cannot be assessed without a documented de novo report.
PP1	Not assessed	No segregation data are available for NM_000455.5:c.249G>A. No publications or case records document co-segregation of this variant with disease in affected family members.
PP2	N/A	PP2 applies to missense variants in genes with a low rate of benign missense variation. NM_000455.5:c.249G>A is a synonymous variant (p.Lys83=), not a missense variant.
PP3	Not met	No in silico predictors support pathogenicity for NM_000455.5:c.249G>A. SpliceAI predicts no splice impact (max delta=0.00). REVEL and BayesDel scores are not available for this synonymous variant. No HCI prior probability is available for STK11.	spliceai
PP4	Not assessed	No patient phenotype or clinical data are available in this case to assess whether the proband's phenotype is specific for STK11-associated disease (Peutz-Jeghers syndrome).
PP5	Not met	ClinVar classifies NM_000455.5:c.249G>A as Likely benign (ClinVar ID 486990, review status: criteria provided, single submitter). PP5 requires a reputable source to report the variant as pathogenic; the ClinVar consensus is benign/likely benign.	clinvar
BA1	Not met	The maximum allele frequency of NM_000455.5:c.249G>A in gnomAD v2.1 is 0.0016% (European non-Finnish) and in gnomAD v4.1 is 0.0016% (Remaining individuals). Both are far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	The maximum allele frequency of NM_000455.5:c.249G>A is 0.0016% in gnomAD, which is below the 0.3% BS1 threshold for a dominant disorder such as Peutz-Jeghers syndrome.	gnomad_v2 gnomad_v4
BS2	Not assessed	No data are available regarding observation of NM_000455.5:c.249G>A in healthy adults with full penetrance expected. While gnomAD contains population data, the age and phenotype of carriers are unknown.
BS3	Not met	No functional studies demonstrating a benign effect have been identified for NM_000455.5:c.249G>A. While SpliceAI predicts no splice impact (delta=0.00), BS3 requires experimental functional evidence, not solely in silico predictions.	spliceai
BS4	Not assessed	No segregation data are available for NM_000455.5:c.249G>A. BS4 requires lack of segregation in affected family members, which cannot be evaluated without family studies.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. NM_000455.5:c.249G>A is a synonymous variant, not a missense variant.
BP2	Not assessed	No data are available regarding observation of NM_000455.5:c.249G>A in trans with a pathogenic STK11 variant. STK11-associated Peutz-Jeghers syndrome is autosomal dominant, making in trans observation less informative, but the data are unavailable in any case.
BP4	Met	Multiple lines of computational evidence suggest NM_000455.5:c.249G>A has no deleterious impact. SpliceAI predicts no splice alteration (max delta=0.00). REVEL and BayesDel are not applicable to synonymous variants, which is itself consistent with a lack of predicted functional effect.	spliceai
BP5	Not assessed	No data are available regarding an alternative molecular cause of disease in the proband. BP5 cannot be assessed without clinical context indicating a different established cause for the phenotype.
BP6	Met	ClinVar classifies NM_000455.5:c.249G>A as Likely benign/Benign with consensus across 5 clinical laboratories (Ambry Genetics, Color Health, Invitae/Labcorp, All of Us, Myriad Genetics). Although review status is criteria provided single submitter per submission, the aggregate agreement of 5 independent clinical laboratories provides reputable source evidence for a benign classification.	clinvar
BP7	Met	NM_000455.5:c.249G>A is a synonymous variant (p.Lys83=) for which SpliceAI predicts no impact on splicing (max delta score=0.00). There is no evidence of an effect on the splice consensus sequence or creation of a cryptic splice site. The variant meets BP7 criteria for a synonymous variant with no predicted splice alteration.	spliceai
BP3	N/A	BP3 applies to in-frame indels in repetitive regions. NM_000455.5:c.249G>A is a single-nucleotide substitution, not an in-frame indel.
PM3	N/A	STK11-associated Peutz-Jeghers syndrome is an autosomal dominant disorder. PM3 is applicable only to recessive disorders where a variant is detected in trans with a pathogenic variant.
PM4	N/A	PM4 applies to protein length changes from in-frame indels or stop-loss variants. NM_000455.5:c.249G>A is a synonymous single-nucleotide substitution that does not alter protein length.

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