Classification rationale

BA1BS1BP4 Benign

STK11 c.369G>A synonymous · exon 2

BA1 (Stand-alone Benign): allele frequency 2.117% in gnomAD African/African American, exceeding the >1% population threshold. BS1 (Strong Benign): ancestry-specific allele frequency 2.117% (gnomAD v4.1), exceeding the >0.3% threshold. BP4 (Supporting): SpliceAI max delta 0.003, below the <0.1 threshold, indicating no splice impact. Under generic ACMG/AMP 2015 combination rules, BA1 alone is sufficient for Benign.

BA1 + BS1 + BP4 → Benign

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

STK11 NM_000455.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 17 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

✓

BA1 stand-alone Benign

Met (stand-alone benign): gnomAD African/African American allele frequency is 2.117% (23 homozygotes), exceeding the >1% BA1 threshold.

gnomAD v4.1 reports NM_000455.4:c.369G>A / 19-1218495-G-A at overall AF 0.0011403893685961559 (1,840/1,613,484 alleles) and African/African American AF 0.021171423241932476 (1,589/75,054 alleles; 23 homozygotes).gnomAD v2.1 reports overall AF 0.002011426615025785 and African/African American AF 0.021255479282110662 (514/24,182 alleles; 7 homozygotes).gnomAD-Canada v1.0 reports AF 0.0016835016835016834 (31/18,414 alleles; 1 homozygote); its African population AF is 0.028431372549019607 (29/1,020 alleles; 1 homozygote).

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

BS1 strong Benign

Met (strong benign): ancestry-specific frequency reaches 2.117% (African/African American, gnomAD v4.1), well above the >0.3% BS1 threshold.

gnomAD v4.1 reports African/African American AF 0.021171423241932476 (1,589/75,054 alleles; 23 homozygotes), well above 0.003.gnomAD v2.1 reports African/African American AF 0.021255479282110662 (514/24,182 alleles; 7 homozygotes), well above 0.003.gnomAD-Canada v1.0 reports African population AF 0.028431372549019607 (29/1,020 alleles; 1 homozygote), also above 0.003.

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (supporting): SpliceAI max delta is 0.003, well below the <0.1 threshold for BP4.

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.003).Generic ACMG fallback rule: SpliceAI max delta < 0.1 -> BP4 (supporting) for non-missense (synonymous/intronic/non-canonical-splice-position) variants.REVEL score not found (null) and BayesDel score not found (null) in prefetch for this variant; in any case both are missense-path predictors inapplicable to this synonymous variant, and BayesDel additionally has no verified published calibration threshold available to this pipeline.

spliceai ↗

Assessed · not applied · 4 not met · 13 not assessed

Pathogenic

PS2 Not assessed: no proband or parental testing data (e.g., de novo observation) was available for this variant.

PS3 Not assessed: no functional assay data (kinase activity, splicing, or other validated studies) was available for this variant.

PS4 Not assessed: no case-control study or affected-case series for this exact variant was available.

PM2 Not met: the variant is present in gnomAD at ~0.114% (v4.1) overall with 25 homozygotes, above the <0.1% rarity threshold.

PM3 Not assessed: no affected-proband observations, second pathogenic allele, or phase information was available.

PM6 Not assessed: no report of this variant arising de novo, with parental testing absent.

PP1 Not assessed: no affected or unaffected relatives with informative genotype data were reported, so cosegregation could not be evaluated.

PP3 Not met: SpliceAI max delta is 0.003, far below the >0.2 threshold required for PP3.

PP4 Not assessed: no patient phenotype or clinical findings establishing a Peutz-Jeghers syndrome-specific presentation were provided.

PP5 Not met: the ClinVar record has no expert-panel submission (0), and laboratory assertions alone cannot support PP5.

Benign

BS2 Not assessed: homozygotes exist (25 in gnomAD v4.1), but their clinically unaffected status could not be confirmed.

BS3 Not assessed: no functional assay demonstrating normal or wild-type activity was available for this variant.

BS4 Not assessed: no affected relatives lacking the variant were documented, so absence of segregation could not be shown.

BP2 Not assessed: no observation of this variant in trans or in cis with a pathogenic variant was documented.

BP5 Not assessed: no alternative molecular diagnosis explaining the patient's phenotype was documented.

BP6 Not met: no ClinVar expert-panel benign assertion exists for this variant (0 expert-panel submissions).

BP7 Not assessed: splice impact is minimal, but no nucleotide-conservation metric was available to complete the required pair of conditions.

N/A · 8 PVS1 · PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 0.00114039; MAF= 0.11404%, 1840/1613484 alleles, homozygotes = 25) and has highest observed frequency in the African/African American population (AF= 0.0211714; MAF= 2.11714%, 1589/75054 alleles, homozygotes = 23); grpmax FAF= 0.0203047.

v2.1

This variant is present in gnomAD v2.1 (AF= 0.00201143; MAF= 0.20114%, 564/280398 alleles, homozygotes = 7) and has highest observed frequency in the African/African American population (AF= 0.0212555; MAF= 2.12555%, 514/24182 alleles, homozygotes = 7); grpmax FAF= 0.0191609.

🇨🇦 CA

This variant is present in gnomAD-Canada v1.0 (AF= 0.0016835016835016834, 31/18414 alleles, homozygotes = 1).

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.11% · 1840 / 1,613,484
25 hom · FAF 2%

African/African American 1589 / 75,054	2.1% 23 hom
Remaining individuals 127 / 62,470	0.2% 1 hom
Admixed American 98 / 60,032	0.16% 1 hom
Middle Eastern 2 / 6,060	0.033%
South Asian 9 / 91,086	0.0099%
European (non-Finnish) 15 / 1,179,754	0.0013%

+ 4 not observed (European (Finnish), Amish, East Asian, Ashkenazi Jewish)

gnomAD v2.1

0.2% · 564 / 280,398
7 hom · FAF 1.9%

African/African American 514 / 24,182	2.1% 7 hom
Admixed American 37 / 35,366	0.1%
Remaining individuals 7 / 7,136	0.098%
South Asian 3 / 30,600	0.0098%
European (non-Finnish) 3 / 128,256	0.0023%

+ 3 not observed (Ashkenazi Jewish, East Asian, European (Finnish))

gnomAD Canada 🇨🇦

0.17% · 31 / 18,414
1 hom · FAF 2%

African/African American 29 / 1,020	2.8% 1 hom
Latino/Admixed American 1 / 838	0.12%
European (non-Finnish) 1 / 11,734	0.0085%

+ 6 not observed (Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, Remaining individuals, South Asian)

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Benign (13 clinical laboratories) and as Likely benign (5 clinical laboratories). (ClinVarID = 141198)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104641676, n = 3 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

25741868 ↗ Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology. CLINVAR

25356965 ↗ ACMG policy statement: updated recommendations regarding analysis and reporting of secondary findings in clinical genome-scale sequencing. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

26389210 ↗ Genetics of Breast and Gynecologic Cancers (PDQ®): Health Professional Version. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Versi CLINVAR

27854360 ↗ Recommendations for reporting of secondary findings in clinical exome and genome sequencing, 2016 update (ACMG SF v2.0): a policy statement of the American College of Medical Genetics and Genomics. CLINVAR

28492532 ↗ Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria. CLINVAR