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 applied · 18 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate review Pathogenic

Population frequency is below the 0.1% rarity threshold used for this non-VCEP review: gnomAD v2.1 AF is 0.00074% (2/269894), gnomAD v4.1 AF is 0.00019% (3/1609476), the highest observed subpopulation frequency is 0.00875% in gnomAD v2.1 African/African American samples, and the variant is absent from gnomAD-Canada.

gnomAD v2.1 total AF 7.41032e-06highest subpopulation AF 8.75044e-05.gnomAD v4.1 total AF 1.86396e-06

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting review Benign

Multiple computational results support a benign effect. SpliceAI predicts no significant splice impact with a max delta score of 0.01, below a 0.2 splice-concern threshold; REVEL is 0.15, consistent with a low missense deleteriousness prediction; and BayesDel is negative at -0.30256, arguing against a damaging effect.

SpliceAI max delta score 0.01.REVEL score 0.15.BayesDel score -0.30256.

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No established pathogenic variant causing the same amino acid change was identified, so PS1 was not assessed.

PS2 No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.

PS3 No well-established functional studies demonstrating a damaging effect of this specific variant were identified.

PS4 This variant has been reported in ClinVar only as a variant of uncertain significance by single submitters, and no case-control or statistically increased prevalence data were identified.

PM1 This variant does not lie in a statistically significant hotspot, and no evidence was identified that codon 17 is a well-established critical functional residue without benign variation.

PM6 No assumed de novo occurrence without full parental confirmation was identified for this variant.

PP1 No segregation data were identified for this variant.

PP2 Available evidence was insufficient to determine whether STK11 missense variants are sufficiently enriched among pathogenic variants at this gene to support PP2 for this variant.

PP3 Available computational evidence does not support a damaging effect.

PP4 No phenotype or family history evidence was identified showing a highly specific clinical presentation attributable to this variant.

Benign

BA1 Population frequency does not meet the stand-alone benign threshold of greater than 1%.

BS1 Population frequency does not exceed the benign strong threshold of greater than 0.3%.

BS2 No evidence was identified showing this variant in healthy adult individuals in a manner sufficient for BS2.

BS3 No well-established functional studies demonstrating normal protein function for this specific variant were identified.

BS4 No lack-of-segregation data were identified for this variant.

BP1 Available evidence was insufficient to conclude that a missense change in STK11 should be down-weighted under BP1 for this variant.

BP2 No phase data with another pathogenic variant were identified for this variant.

BP5 No alternate molecular explanation for the relevant phenotype was identified.

N/A · 8 PVS1 · PM3 · PM4 · PM5 · PP5 · BP3 · BP6 · BP7

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

Re-run this variant?