Classification rationale

PM2 BP4 VUS

STK11 c.49C>G

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.¹ 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.² 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.³

PM2 + BP4 → VUS

1 clinvar ↗

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 spliceai ↗revelbayesdel

Gene diagram · NM_000455.5 · variants mapped to exon structure

STK11 NM_000455.5

Fetching transcript structure from UCSC…

Applied criteria · 2 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

PS

PM

PP

Benign evidence

BA

BS

BP

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.86396e-06; MAF= 0.00019%, 3/1609476 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 2.67294e-05; MAF= 0.00267%, 2/74824 alleles, homozygotes = 0); grpmax FAF= 4.44e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 7.41032e-06; MAF= 0.00074%, 2/269894 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 8.75044e-05; MAF= 0.00875%, 2/22856 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00019% · 3 / 1,609,476
0 hom · FAF 0.00044%

African/African American 2 / 74,824	0.0027%
European (non-Finnish) 1 / 1,178,234	8.5e-05%

+ 8 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish)

gnomAD v2.1

0.00074% · 2 / 269,894
0 hom

African/African American

2 / 22,856

0.0088%

+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

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 Uncertain significance (6 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 458049)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.15. BayesDel score = -0.30256.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. STK11, a tumor suppressor and intracellular kinase, is frequently mutated in lung cancer.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

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 · 9 PMIDs not cited in assessment

25645574 ↗ ACG clinical guideline: Genetic testing and management of hereditary gastrointestinal cancer syndromes. CLINVAR

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

31672839 ↗ Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. CLINVAR

15604628 ↗ Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors. CLINVAR

20301443 ↗ Peutz-Jeghers Syndrome. CLINVAR

23788249 ↗ ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing. 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

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