Variant classification summary

NM_000455.5:c.22C>G

STK11 · NP_000446.1:p.(Gln8Glu) · NM_000455.5

GRCh37: chr19:1206934 C>G · GRCh38: chr19:1206935 C>G

Gene: STK11 Transcript: NM_000455.5

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.(Gln8Glu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The STK11 c.22C>G (p.Gln8Glu) variant has been reported in ClinVar as uncertain significance by five clinical laboratory submissions.

2

This variant is very rare in population databases, with AF 4.6322e-06 in gnomAD v2.1 and AF 2.50785e-06 in gnomAD v4.1, supporting rarity but not a benign frequency threshold.

3

Computational evidence supports no significant impact on splicing or protein function, with SpliceAI max delta score 0.00, REVEL 0.032, and BayesDel -0.435498.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	STK11 loss of function is an established disease mechanism, but NM_000455.5:c.22C>G is a missense variant p.(Gln8Glu)/p.(Q8E) and does not fall into the generic PVS1 null-variant categories of nonsense, frameshift, or canonical +/-1,2 splice variants.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No evidence was identified showing that this amino acid change has already been established as pathogenic from a different nucleotide change.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with parental confirmation was identified for this variant.
PS3	Not assessed	No validated functional study demonstrating a damaging effect of this specific STK11 variant was identified.
PS4	Not assessed	This variant is present in ClinVar, but no proband count, case-control enrichment, or other case-level data sufficient to show increased prevalence in affected individuals was identified.	clinvar
PM1	Not met	Available evidence does not place p.(Gln8Glu) in a statistically significant hotspot, and no critical STK11 functional region at residue 8 was identified from the reviewed sources.	hotspots
PM2	Met	This variant is very rare in population databases, with AF 4.6322e-06 in gnomAD v2.1 and AF 2.50785e-06 in gnomAD v4.1, both below the 0.1% PM2 threshold used for non-VCEP review.	gnomad_v2 gnomad_v4
PM3	N/A	PM3 is not applicable because STK11-related Peutz-Jeghers syndrome is not assessed here as a recessive disorder requiring trans observations.	PMID:20301443 PMID:25645574
PM4	N/A	PM4 is not applicable because this variant is a missense substitution and does not change protein length through an in-frame insertion, deletion, or stop-loss event.	pvs1_variant_assessment
PM5	Not assessed	No established pathogenic missense comparator at codon 8 was identified from the reviewed evidence.	clinvar
PM6	Not assessed	No assumed de novo occurrence without full parental confirmation was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant in affected family members.
PP2	Not assessed	The reviewed evidence did not provide a gene-specific basis to apply PP2 for this missense variant.
PP3	Not met	Available computational evidence does not support a deleterious effect: SpliceAI predicts no significant splice impact with max delta score 0.00, REVEL is low at 0.032, and BayesDel is negative at -0.435498.	spliceai revel bayesdel
PP4	Not assessed	No patient-specific phenotype information was available to determine whether the clinical presentation is highly specific for STK11-related disease.	PMID:20301443 PMID:25645574
PP5	Not met	ClinVar reports this variant as uncertain significance rather than as a pathogenic or likely pathogenic variant from a reputable source.	clinvar
BA1	Not met	Population frequency does not reach the standalone benign threshold: AF is 4.6322e-06 in gnomAD v2.1 and 2.50785e-06 in gnomAD v4.1, both far below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not exceed the strong benign threshold: AF is 4.6322e-06 in gnomAD v2.1 and 2.50785e-06 in gnomAD v4.1, both far below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in well-phenotyped healthy adult individuals in a way that would strongly argue against pathogenicity.	gnomad_v2 gnomad_v4
BS3	Not assessed	No validated functional study demonstrating normal STK11 function for this specific variant was identified.
BS4	Not assessed	No non-segregation data were identified for this variant.
BP1	Not assessed	The reviewed evidence did not provide a sufficient gene-specific basis to apply BP1 to this missense variant.
BP2	Not assessed	No phase data or second-variant data were identified to support BP2.
BP3	N/A	BP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region.	pvs1_variant_assessment
BP4	Met	Multiple computational results support no significant impact: SpliceAI predicts no significant splice effect with max delta score 0.00, REVEL is 0.032, and BayesDel is -0.435498, together arguing against a deleterious effect.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular explanation for an affected individual's phenotype was identified.
BP6	Not met	ClinVar does not report this variant as benign or likely benign from a reputable source; the available submissions classify it as uncertain significance.	clinvar
BP7	N/A	BP7 is not applicable because this is a missense variant rather than a synonymous or deep intronic change.	spliceai

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