NM_000455.5:c.112C>G

STK11 · NP_000446.1:p.(Pro38Ala) · NM_000455.5

GRCh37: chr19:1207024 C>G · GRCh38: chr19:1207025 C>G

Gene: STK11 Transcript: NM_000455.5

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.(Pro38Ala)

gnomAD AF

5.576885421030063e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000455.5:c.112C>G (p.Pro38Ala) in STK11 is a missense variant with no functional, segregation, or case-control data available.

The variant is extremely rare in population databases, absent from gnomAD v2.1 and present in gnomAD v4.1 at AF=5.58e-06 (9/1,613,804 alleles), meeting PM2 at supporting level.

Multiple in silico tools predict no deleterious effect: SpliceAI max delta=0.0, REVEL=0.328, BayesDel=-0.085, meeting BP4 at supporting benign level.

ClinVar reports the variant as Uncertain Significance by multiple clinical laboratories (Variation ID 458014) with no expert panel classification.

The variant does not reside in a known functional domain or mutational hotspot. No same-residue pathogenic comparator (PM5) or de novo evidence (PS2/PM6) was identified.

Overall, the available evidence is limited to population frequency data (PM2_supporting) and computational predictions (BP4_supporting_benign), which offset each other. The variant remains a Variant of Uncertain Significance.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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.112C>G is a missense variant (p.Pro38Ala), not a null variant. It does not fall into the nonsense, frameshift, or canonical splice consensus categories required for PVS1 application under the ClinGen SVI PVS1 framework (PMC6185798).	pvs1_variant_assessment pvs1_gene_context
PS1	Not assessed	No evidence of a different pathogenic missense change at the same amino acid residue (Pro38) was identified. No comparator variant with a different amino acid substitution at Pro38 classified as pathogenic was found in ClinVar or the literature.
PS2	Not assessed	No de novo reports were identified for NM_000455.5:c.112C>G in the available literature or ClinVar submissions.
PS3	Not assessed	No well-established functional studies demonstrating a damaging effect for NM_000455.5:c.112C>G (p.Pro38Ala) were identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional evidence. No publications with functional characterization of this variant were found.	oncokb
PS4	Not met	No case-control studies or cohort analyses demonstrate enrichment of NM_000455.5:c.112C>G in affected individuals. The variant is observed in 9/1,613,804 alleles in gnomAD v4.1 (AF = 5.58e-06). No published studies document the variant in multiple unrelated affected individuals.	gnomad_v4 clinvar
PS5	Not assessed	No expert panel or reputable source has classified NM_000455.5:c.112C>G as pathogenic. All ClinVar submissions classify the variant as Uncertain Significance from single submitters, which does not meet the threshold for PS5.	clinvar
PM1	Not assessed	The variant resides at codon 38 (p.Pro38Ala), which is in the N-terminal region of STK11, upstream of the kinase domain (residues ~49-309). The Cancer Hotspots database indicates this residue is not in a statistically significant somatic hotspot. Without a VCEP-defined critical functional domain map for STK11, PM1 cannot be reliably applied in the generic ACMG framework.
PM2	Met	NM_000455.5:c.112C>G is absent from gnomAD v2.1 and present at extremely low frequency in gnomAD v4.1 (AF = 5.58e-06; 9/1,613,804 alleles, no homozygotes). This is well below the 0.1% threshold for PM2 in the generic ACMG/AMP framework. The variant is also absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4
PM5	Not assessed	No confirmed pathogenic missense variant at the same amino acid residue (Pro38) with a different amino acid substitution was identified. The automated PM5 candidate search returned no candidates.	pm5_candidates
PM6	Not assessed	No de novo reports were identified for NM_000455.5:c.112C>G. PM6 requires confirmed de novo occurrence with both parental relationships confirmed.
PP1	Not assessed	No segregation data are available for NM_000455.5:c.112C>G. No family studies documenting co-segregation with disease were identified in the literature.
PP2	N/A	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease, supported by gene-specific constraint metrics. No HCI prior or missense constraint score is available for STK11 to support PP2 application in the generic ACMG framework.
PP3	Not met	Multiple in silico tools do not support a deleterious effect for NM_000455.5:c.112C>G (p.Pro38Ala). SpliceAI predicts no splice impact (max delta = 0.0). REVEL score is 0.328, below commonly used pathogenic thresholds (>0.5). BayesDel score is -0.085 (negative, favoring a benign interpretation). Multiple lines of computational evidence do not support pathogenicity.	spliceai revel bayesdel
PP4	Not assessed	No specific phenotypic data are available for individuals carrying NM_000455.5:c.112C>G. While STK11 is associated with Peutz-Jeghers syndrome, the variant's extremely low population frequency precludes phenotype-genotype correlation without individual-level clinical data.
PP5	Not assessed	No reputable source has classified NM_000455.5:c.112C>G as pathogenic. All ClinVar submissions from clinical laboratories classify this variant as Uncertain Significance. The ClinVar-cited literature (PMID:33471991) is a breast cancer association study without confirmed variant-level evidence for this specific variant.	clinvar
BA1	Not met	The allele frequency of NM_000455.5:c.112C>G in gnomAD v4.1 is 5.58e-06 (0.00056%), far below the 1% BA1 threshold. This does not support classification as benign based on population frequency.	gnomad_v4
BS1	Not met	The allele frequency of NM_000455.5:c.112C>G in gnomAD v4.1 is 5.58e-06 (0.00056%), well below the 0.3% BS1 threshold. This does not support classification as benign based on population frequency.	gnomad_v4
BS2	Not assessed	While 9 alleles are observed in gnomAD v4.1 (no homozygotes), the number is too low to assess whether the variant is observed in healthy adults at a frequency expected for a fully penetrant disorder. Individual phenotype data for gnomAD carriers are not available.
BS3	Not assessed	No well-established functional studies demonstrating no damaging effect for NM_000455.5:c.112C>G (p.Pro38Ala) were identified. No publications with functional characterization of this specific variant were found.
BS4	Not assessed	No segregation data are available to assess lack of segregation with disease. No family studies were identified for NM_000455.5:c.112C>G.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. While STK11 has pathogenic truncating variants, it also has well-established pathogenic missense variants, particularly in the kinase domain. A missense change in STK11 does not automatically qualify for BP1.
BP2	Not assessed	No observation of NM_000455.5:c.112C>G in trans with a known pathogenic STK11 variant was identified. No phase data are available from gnomAD or the literature.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. SpliceAI predicts no splice impact (max delta = 0.0). REVEL score is 0.328, below pathogenic thresholds. BayesDel score is -0.085 (negative, favoring a benign interpretation). These findings meet BP4 at supporting benign level.	spliceai revel bayesdel
BP5	Not assessed	No cases have been identified where an individual carrying NM_000455.5:c.112C>G has an alternate molecular basis for disease.
BP6	Not assessed	No reputable source has classified NM_000455.5:c.112C>G as benign. All ClinVar entries are VUS. No expert panel benign classification is available.	clinvar
BP7	Not met	BP7 applies to synonymous variants with no predicted splice impact. NM_000455.5:c.112C>G is a missense variant (p.Pro38Ala), resulting in a non-conservative amino acid substitution from proline to alanine. BP7 does not apply to missense variants.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This variant is a single-nucleotide substitution.
PM3	N/A	No data on observation in trans with a pathogenic variant for a recessive disorder. STK11-associated Peutz-Jeghers syndrome is autosomal dominant.
PM4	N/A	PM4 applies to non-frameshift deletions/insertions causing protein length change. This variant is a single-nucleotide substitution resulting in a missense change.

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