NM_000455.5:c.49C>G

STK11 · NP_000446.1:p.(Leu17Val) · NM_000455.5

GRCh37: chr19:1206961 C>G · GRCh38: chr19:1206962 C>G

Gene: STK11 Transcript: NM_000455.5

Final call

VUS

PM2 moderate BP4 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.(Leu17Val)

gnomAD AF

1.8639606927969104e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

The STK11 c.49C>G (p.Leu17Val) variant has not been observed in somatic cancers in COSMIC and has been reported in ClinVar only as a variant of uncertain significance by single submitters.

This variant is rare in population databases, with gnomAD v2.1 AF 0.00074% (2/269894), gnomAD v4.1 AF 0.00019% (3/1609476), a highest observed subpopulation frequency of 0.00875% in gnomAD v2.1 African/African American samples, and no observation in gnomAD-Canada.

Computational evidence supports a benign effect, with SpliceAI max delta 0.01 indicating no significant splice impact, REVEL 0.15 indicating a low deleteriousness prediction, and BayesDel -0.30256 arguing against a damaging missense effect.

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	This is a missense variant, and the generic PVS1 framework does not apply because it is not a nonsense, frameshift, or canonical +/-1,2 splice variant even though STK11 loss of function is an established disease mechanism.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not assessed	No established pathogenic variant causing the same amino acid change was identified, so PS1 was not assessed.
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect of this specific variant were identified.	oncokb
PS4	Not met	This variant has been reported in ClinVar only as a variant of uncertain significance by single submitters, and no case-control or statistically increased prevalence data were identified.	clinvar
PM1	Not met	This variant does not lie in a statistically significant hotspot, and no evidence was identified that codon 17 is a well-established critical functional residue without benign variation.	hotspots
PM2	Met	Population frequency is below the 0.1% rarity threshold used for this non-VCEP review: gnomAD v2.1 AF is 0.00074% (2/269894), gnomAD v4.1 AF is 0.00019% (3/1609476), the highest observed subpopulation frequency is 0.00875% in gnomAD v2.1 African/African American samples, and the variant is absent from gnomAD-Canada.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 is not applicable because no recessive disease context or trans configuration evidence was identified for this STK11 variant.
PM4	N/A	PM4 is not applicable because this variant is a missense substitution and does not cause a protein length change or in-frame exon-level alteration.
PM5	N/A	PM5 was not applied because classic same-residue PM5 eligibility could not be confirmed safely and no validated pathogenic same-residue comparator variants were identified.	pm5_candidates
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.
PP2	Not assessed	Available evidence was insufficient to determine whether STK11 missense variants are sufficiently enriched among pathogenic variants at this gene to support PP2 for this variant.
PP3	Not met	Available computational evidence does not support a damaging effect. SpliceAI predicts no significant splice impact with a max delta score of 0.01, which is below a 0.2 splice-concern threshold, REVEL is 0.15, and BayesDel is -0.30256; together these findings do not support PP3.	spliceai revel bayesdel
PP4	Not assessed	No phenotype or family history evidence was identified showing a highly specific clinical presentation attributable to this variant.
PP5	N/A	PP5 was not used. ClinVar contains only single-submitter uncertain significance assertions without validated primary evidence that would support pathogenic classification.	clinvar
BA1	Not met	Population frequency does not meet the stand-alone benign threshold of greater than 1%. The highest observed frequency is 0.00875% in gnomAD v2.1 African/African American samples, well below 1%.	gnomad_v2 gnomad_v4
BS1	Not met	Population frequency does not exceed the benign strong threshold of greater than 0.3%. The highest observed frequency is 0.00875% in gnomAD v2.1 African/African American samples, which is below 0.3%.	gnomad_v2 gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals in a manner sufficient for BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional studies demonstrating normal protein function for this specific variant were identified.	oncokb
BS4	Not assessed	No lack-of-segregation data were identified for this variant.
BP1	Not assessed	Available evidence was insufficient to conclude that a missense change in STK11 should be down-weighted under BP1 for this variant.
BP2	Not assessed	No phase data with another pathogenic variant were identified for this variant.
BP3	N/A	BP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region.
BP4	Met	Multiple computational results support a benign effect. SpliceAI predicts no significant splice impact with a max delta score of 0.01, below a 0.2 splice-concern threshold; REVEL is 0.15, consistent with a low missense deleteriousness prediction; and BayesDel is negative at -0.30256, arguing against a damaging effect.	spliceai revel bayesdel
BP5	Not assessed	No alternate molecular explanation for the relevant phenotype was identified.
BP6	N/A	BP6 was not used. No reputable source benign or likely benign assertion with sufficient supporting evidence was identified; ClinVar shows only uncertain significance submissions.	clinvar
BP7	N/A	BP7 is not applicable because this is a missense variant, not a synonymous or deep intronic change.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.