Final classification

Pathogenic

PVS1PM2PP4

STK11

c.658C>T

p.Gln220Ter

nonsense · exon 5

Gene context NCBI Gene ↗ OncoKB ↗

STK11 encodes a serine/threonine kinase that acts as a tumor suppressor, regulating cell polarity, energy metabolism, and stress responses through the AMPK signaling pathway. Germline mutations in this gene cause Peutz-Jeghers syndrome, an inherited condition marked by gastrointestinal polyps, mucocutaneous pigmentation, and an elevated risk of several cancers. Loss of STK11 function also occurs in cancers of the lung, pancreas, breast, cervix, liver, and other tissues, where it promotes tumor growth.

This variant

Loss of STK11 tumor-suppressor function is the established mechanism underlying germline Peutz-Jeghers syndrome and contributes to susceptibility to multiple cancers.

Transcript

NM_000455.4

HGVS · transcript:coding

NM_000455.4:c.658C>T

GRCh38

chr19:1220641 C>T

GRCh37

chr19:1220640 C>T

Pathogenic: PVS1 (very strong) plus PM2 and PP4 (supporting) satisfy the generic ACMG/AMP rule for one very strong criterion with two supporting criteria.

Classification rationale

PVS1PM2PP4 Pathogenic

STK11 c.658C>T nonsense · exon 5

PVS1 very strong: c.658C>T creates p.Gln220Ter in exon 5 of 9 and truncates STK11 well before its terminal exon. PM2 supporting: the variant is absent from evaluated population datasets, with gnomAD v4.1 frequency 0. PP4 supporting: the exact variant was reported in a child with Peutz-Jeghers syndrome and buccal freckling.

PVS1 + PM2 + PP4 → Pathogenic

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000455.4 · variants mapped to exon structure

STK11 NM_000455.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 12 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

PVS1 very strong Pathogenic

Met, very strong: c.658C>T creates p.Gln220Ter in exon 5 of 9, far upstream of the terminal junction and truncating the 434-residue STK11 protein.

The generic ClinGen SVI PVS1 framework in PMC6185798 was used because no STK11-specific VCEP or CSPEC specification was available.VariantValidator identifies NM_000455.4:c.658C>T as a nonsense variant producing NP_000446.1:p.(Gln220Ter) in exon 5 of the RefSeq-selected nine-exon STK11 transcript; the stop is well upstream of the final exon-exon junction, supporting NMD rather than escape.The predicted protein consequence terminates STK11 at residue 220 of 434, within the central functional region and not in a distal terminal tail; no evidence in the case data indicates a non-critical exon or benign loss-of-function-enriched repeat region.

pvs1_generic_framework ↗PMID:17026623 ↗PMID:9887330 ↗

PM2 supporting Pathogenic

Met at supporting strength: the variant was absent from gnomAD v2.1 and non-cancer subsets, and gnomAD v4.1 showed AF 0 (0/1,608,534).

gnomAD v2.1 reported the variant as absent.The gnomAD v2.1 non-cancer exome-only dataset reported the variant as absent.The gnomAD v3.1 non-cancer genome-only dataset reported the variant as absent.

gnomad_v2 ↗gnomad_v4 ↗

PP4 supporting Pathogenic

Met (supporting): the exact variant was reported in a child with Peutz–Jeghers syndrome and buccal freckling, a characteristic STK11-associated phenotype.

PMID:17026623 Table 1 reports c.658C>T:p.Q220X in patient 4, a female diagnosed with Peutz–Jeghers syndrome at age 3 with buccal freckling.Peutz–Jeghers syndrome with mucocutaneous pigmentation is the characteristic phenotype associated with germline STK11 disease.PMID:9887330 independently reports C658→T in a Peutz–Jeghers syndrome patient, although that patient's family history, pigmentation, and cancer history were unknown.

PMID:17026623 ↗PMID:9887330 ↗

Assessed · not applied · 3 not met · 9 not assessed

Pathogenic

PS2 Not assessed: the variant is reported in a proband, but parental testing and confirmed absence in both parents are not reported.

PS3 Not assessed: no variant-specific functional assay was reported for c.658C>T; the cited study tested other LKB1 alleles.

PS4 Not assessed: exact-variant reports document individual Peutz–Jeghers cases but provide no case-control enrichment statistic or comparison with controls.

PM6 Not assessed: affected-patient reports lack sufficient family and parental information to support presumed de novo occurrence.

PP1 Not assessed: no informative relatives with documented genotype and phenotype are reported for evaluating co-segregation.

Benign

BA1 Not met: gnomAD v4.1 allele frequency was 0 (0/1,608,534), far below the BA1 threshold of >=0.05.

BS1 Not met: gnomAD v4.1 allele frequency was 0 (0/1,608,534), below the generic BS1 threshold of >=0.01.

BS2 Not met: no healthy-adult observation was documented, with 0 alternate alleles and 0 homozygotes in gnomAD v4.1.

BS3 Not assessed: no controlled assay demonstrated preserved STK11 function for p.Gln220Ter, and available functional tests used other alleles.

BS4 Not assessed: no informative unaffected relatives with documented carrier status are available to demonstrate non-segregation.

BP2 Not assessed: no additional pathogenic variant or cis/trans phase information is documented for the c.658C>T proband.

BP5 Not assessed: no alternate molecular etiology or BP5-specific benign likelihood-ratio result is documented for the exact variant.

N/A · 13 PS1 · PM1 · PM3 · PM4 · PM5 · PP2 · PP3 · PP5 · BP1 · BP3 · BP4 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0; MAF= 0.00000%, 0/1608534 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 0; MAF= 0.00000%, 0/74952 alleles, homozygotes = 0).

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / 1,608,534
0 hom

Not observed in any ancestry group.

+ 10 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (8 clinical laboratories). (ClinVarID = 428776)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.10). BayesDel score = 0.65.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Hotspot

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58820792, n = 15 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 6 further PMIDs triaged but not cited — see Sources & references.

An updated mutation spectrum in an Australian series of PJS patients provides further evidence for only one gene locus.

PMID 17026623 ↗ CLINVAR · functional

Searched

c.658C>TNP_000446.1:p.(Q220*)

Found

The paper reports STK11 c.658C>T (p.Q220X, corresponding to NP_000446.1:p.(Q220*)) in patient 4 of the cohort. The patient was female, diagnosed with Peutz–Jeghers syndrome at age 3, and had buccal freckling. The variant was listed among the paper's pathogenic STK11 mutations and classified by the authors as a substitution resulting in a premature termination codon.

Variant

✓ Names this variant — characterised directly

Applied to

→PVS1 very strong

Direct variant-level confirmation of the premature termination consequence and occurrence in a Peutz–Jeghers syndrome cohort.

→PP4 supporting

The exact variant is reported in a Peutz–Jeghers syndrome patient with buccal freckling, supporting phenotype specificity.

4 c. 658C.T:p.Q220X Female 3 Buccal Freckling

Location Table 1, Pathogenic mutations, patient 4 · Context Mutation analysis of 33 unrelated Australian Peutz–Jeghers syndrome probands using denaturing high-performance liquid chromatography, direct DNA sequencing, and multiplex ligation-dependent probe amplification. · full text

Mutations and impaired function of LKB1 in familial and non-familial Peutz-Jeghers syndrome and a sporadic testicular cancer.

PMID 9887330 ↗ CLINVAR · functional

Searched

c.658C>TC658→TNP_000446.1:p.(Q220*)Gln→stop

Found

The paper reports the STK11/LKB1 germline variant C658→T in patient P12 and describes it as a Gln-to-stop change that compromises the LKB1 open reading frame and is predicted to produce a truncated protein. The paper does not report a variant-specific functional assay for C658→T.

Variant

✓ Names this variant — characterised directly

Applied to

→PVS1 very strong

Directly supports the nonsense change as an open-reading-frame-compromising truncating STK11/LKB1 variant.

→PP4 supporting

The exact variant is independently reported in a Peutz–Jeghers syndrome patient, although detailed phenotype information is incomplete.

Fifteen mutations compromised the LKB1 open reading frame (ORF), and involved small deletions (e.g. P20 and P8; Fig. 1A and C, respectively) and point mutations (e.g. P28 and P12; Fig. 1B and D, respectively) in all coding exons except exons 2 and 9.

Location Results, Table 1 and paragraph beginning ‘Fifteen mutations compromised the LKB1 open reading frame’; Figure 1D legend · Context Germline mutation screening by genomic sequencing of the nine coding LKB1 exons in 33 unrelated Peutz–Jeghers syndrome patients; the P12 variant was identified by sequencing. No C658→T-specific functional assay was reported. · full text

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 6 PMIDs not cited in assessment

19340305 ↗ Somatic LKB1 mutations promote cervical cancer progression. ONCOKB

19892943 ↗ Structure of the LKB1-STRAD-MO25 complex reveals an allosteric mechanism of kinase activation. ONCOKB

21516316 ↗ The role of LKB1 in lung cancer. ONCOKB

24652667 ↗ STK11 domain XI mutations: candidate genetic drivers leading to the development of dysplastic polyps in Peutz-Jeghers syndrome. ONCOKB

25079552 ↗ Comprehensive molecular profiling of lung adenocarcinoma. ONCOKB

9850045 ↗ Pathogenesis of adenocarcinoma in Peutz-Jeghers syndrome. CLINVAR

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