NM_000455.5:c.580G>C

STK11 · NP_000446.1:p.(Asp194His) · NM_000455.5

GRCh37: chr19:1220487 G>C · GRCh38: chr19:1220488 G>C

Gene: STK11 Transcript: NM_000455.5

Final call

VUS

PM1 moderate PM2 moderate PP3 supporting

Variant details

Gene

STK11

Transcript

NM_000455.5

Protein

NP_000446.1:p.(Asp194His)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000455.5:c.580G>C (p.Asp194His) is located in exon 4 of STK11, within the protein kinase domain catalytic loop (DLKPEN motif), a critical functional domain.

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, representing coverage of over 800,000 alleles (PM2_moderate).

Asp194 is a statistically significant hotspot residue in the kinase active site, and no benign missense variants are observed at this codon in population databases (PM1_moderate).

Multiple in silico algorithms predict a deleterious effect: REVEL score 0.943, BayesDel score 0.524 (PP3_supporting).

SpliceAI predicts no significant splice impact (max delta = 0.02), consistent with a missense mechanism rather than splicing disruption.

The variant has been observed in somatic cancers (COSMIC COSV99045288, n=3), which is consistent with a potential oncogenic role but does not directly inform germline pathogenicity.

ClinVar contains two submissions: Uncertain Significance (Invitae, SCV001518979) and Likely Pathogenic (CeGaT, SCV002498394). Neither is from an expert panel.

No de novo observations, cosegregation data, or functional studies specific to p.Asp194His were identified in the literature.

The absence of variant-specific functional data, segregation evidence, and case-control studies limits the certainty of classification.

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.580G>C is a missense variant (p.Asp194His) in exon 4. It is not a nonsense, frameshift, or canonical ±1,2 splice site variant. SpliceAI predicts no significant splice impact (max delta score = 0.02). The variant does not fall into any generic PVS1 null-variant bucket per ClinGen SVI PVS1 recommendations (PMC6185798).	spliceai pvs1_variant_assessment
PS1	Not met	PS1 requires a different nucleotide change at the same codon producing the same amino acid change that is already established as pathogenic. No such comparator variant with a pathogenic classification was identified for p.Asp194His. The ClinVar and literature survey found no alternate nucleotide substitution (e.g., c.580G>A or c.580G>T) at codon 194 producing p.Asp194His with a pathogenic assertion.	clinvar
PS2	Not met	PS2 requires a de novo observation with both maternity and paternity confirmed in a patient with the disease and no family history. No de novo occurrence of NM_000455.5:c.580G>C has been reported in the literature, ClinVar, or other databases. An exploratory literature and database search returned no de novo reports for this variant.	clinvar
PS3	Not met	PS3 requires well-established in vitro or in vivo functional studies demonstrating a damaging effect. No functional assays specifically testing the p.Asp194His (D194H) substitution were identified. OncoKB annotates the variant as 'Likely Oncogenic' with a 'Likely Loss-of-function' context, but this is a bioinformatic prediction rather than direct experimental evidence. Publications PMID:26917230 and PMID:34849607 discuss STK11 functional assessment but do not specifically assay NM_000455.5:c.580G>C in available abstracts.	oncokb
PS4	Not met	PS4 requires the prevalence of the variant in affected individuals to be significantly increased compared to controls. The variant is absent from gnomAD v2.1 and v4.1 (0 alleles). ClinVar records two clinical laboratory submissions (1 Uncertain significance, 1 Likely pathogenic) without patient counts. No case-control study or cohort data quantifying prevalence in Peutz-Jeghers syndrome versus the general population is available.	gnomad_v2 gnomad_v4 clinvar
PS5	Not met	PS5 is a legacy ACMG criterion for when a reputable source reports a variant as pathogenic but the evidence is not independently available. This criterion is rarely applied in modern practice and has been largely superseded. No expert panel or multi-institutional consensus classification of Pathogenic exists for this variant. The single CeGaT Likely Pathogenic classification is insufficient to invoke PS5.	clinvar
PM1	Met	c.580G>C (p.Asp194His) is located in exon 4 within the STK11 serine/threonine protein kinase domain (residues 49-309). Asp194 is a highly conserved catalytic base in the kinase active site (DLKPEN motif). The residue lies in a statistically significant mutational hotspot, and no benign missense variants have been observed at this residue in gnomAD. The variant is situated in a critical, well-established functional domain where pathogenic missense variation is enriched.	gnomad_v2 gnomad_v4
PM2	Met	NM_000455.5:c.580G>C is absent from gnomAD v2.1 (exomes) and gnomAD v4.1 (exomes + genomes), representing a combined survey of over 800,000 alleles without observation. The variant is also absent from gnomAD-Canada v1.0. This complete absence from large population databases meets PM2 at moderate strength under the generic ACMG/AMP framework (allele frequency <0.1%).	gnomad_v2 gnomad_v4
PM5	N/A	PM5 requires a different amino acid change at the same residue that is already established as pathogenic. No pathogenic comparator variants at codon 194 were identified in ClinVar or literature. The pm5_candidates pipeline found zero same-residue candidates.	pm5_candidates clinvar
PM6	Not met	PM6 requires a presumed de novo observation (without confirmation of both parents). No de novo reports — confirmed or presumed — were found for NM_000455.5:c.580G>C in literature, ClinVar, or other databases.	clinvar
PP1	Not met	PP1 requires cosegregation of the variant with disease in multiple affected family members. No family studies or cosegregation data for NM_000455.5:c.580G>C have been reported in the literature.
PP2	Not assessed	PP2 requires a low rate of benign missense variation in the gene where missense variants are a common disease mechanism. STK11 is a tumor suppressor where missense variants are a recognized mechanism of Peutz-Jeghers syndrome, but the HCI prior score is not available for this gene, and population-level missense constraint metrics (e.g., Z-score, missense o/e) were not retrieved. Without these metrics, PP2 cannot be reliably assessed.
PP3	Met	Multiple lines of computational evidence support a deleterious effect. REVEL predicts a highly damaging score of 0.943 (threshold ≥0.75). BayesDel gives a score of 0.524 (threshold >0.27 for deleterious). SpliceAI predicts no splice impact (max delta = 0.02), which does not contradict the missense pathogenicity prediction. Two independent in silico algorithms concur on a damaging prediction, meeting PP3 at supporting strength.	revel bayesdel spliceai
PP4	Not assessed	PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. No proband-specific clinical data (personal or family history) were provided for this case. PP4 cannot be assessed without patient phenotype information.
PP5	Not met	PP5 requires a reputable source (e.g., clinical diagnostic laboratory with established quality systems) to report the variant as pathogenic. In ClinVar, this variant has one Likely Pathogenic classification (CeGaT, single submitter) and one Uncertain Significance classification (Invitae). The split classification and single-submitter status do not constitute a strong, reproducible pathogenic assertion from a reputable source sufficient for PP5. Additionally, PP5 is considered a legacy criterion and is generally discouraged in modern ACMG/AMP interpretation.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in a general population database. NM_000455.5:c.580G>C is absent from gnomAD v2.1 and v4.1 (0 alleles, allele frequency = 0). BA1 is clearly not met.	gnomad_v2 gnomad_v4
BS1	Not met	BS1 requires an allele frequency >0.3% in a general population database. The variant is absent from gnomAD v2.1 and v4.1. BS1 is not met.	gnomad_v2 gnomad_v4
BS2	Not met	BS2 requires observation of the variant in a healthy adult individual for a fully penetrant disorder expected to manifest at an early age. No such observation has been reported for NM_000455.5:c.580G>C. The variant is absent from gnomAD, which precludes identifying healthy adult carriers.	gnomad_v2 gnomad_v4
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect. No functional assays evaluating the p.Asp194His substitution were identified. The OncoKB annotation of 'Likely Loss-of-function' suggests a damaging, not benign, functional consequence. PMID:26917230 and PMID:34849607 discuss STK11 functional assays but do not specifically evaluate p.Asp194His in available abstracts.	oncokb
BS4	Not met	BS4 requires lack of cosegregation of the variant with disease in affected family members (i.e., the variant does not segregate with disease). No family studies or non-segregation data have been reported for NM_000455.5:c.580G>C.
BP1	N/A	BP1 applies when a missense variant is found in a gene where only truncating variants are known to cause disease. STK11 missense variants are a well-established mechanism of Peutz-Jeghers syndrome, and numerous pathogenic missense variants have been reported in ClinVar and the literature. BP1 does not apply.	clinvar
BP2	Not met	BP2 requires observation of the variant in trans with a known pathogenic variant in a gene for a fully penetrant dominant disorder, OR in cis with a pathogenic variant in a recessive disorder. No observation of NM_000455.5:c.580G>C in trans with a pathogenic STK11 variant has been reported. The variant is absent from gnomAD, precluding co-occurrence analysis.	gnomad_v2 gnomad_v4
BP4	Not met	BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. REVEL predicts a damaging score of 0.943 and BayesDel predicts a deleterious score of 0.524. Both in silico predictors suggest a damaging, not benign, effect. BP4 is not met — the computational evidence favors a deleterious effect (see PP3).	revel bayesdel
BP5	Not met	BP5 requires the variant to be found in a case with an alternate molecular basis for disease. No such observation has been reported for NM_000455.5:c.580G>C in a patient with an alternative cause of Peutz-Jeghers syndrome or overlapping phenotype.
BP6	Not met	BP6 requires a reputable source to report the variant as benign or likely benign. In ClinVar, the variant has one Uncertain Significance classification (Invitae) and one Likely Pathogenic classification (CeGaT). No laboratory or expert panel has classified this variant as Benign or Likely Benign.	clinvar
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or the creation of a new splice site. NM_000455.5:c.580G>C is a missense variant (p.Asp194His), not a synonymous variant. BP7 is not applicable.

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