Classification rationale

PM2 BP4 VUS

STK11 c.112C>G

NM_000455.5:c.112C>G (p.Pro38Ala) in STK11 is a missense variant with no functional, segregation, or case-control data available. The variant is extremely rare in population databases, absent from gnomAD v2.1 and present in gnomAD v4.1 at AF=5.58e-06 (9/1,613,804 alleles), meeting PM2 at supporting level.¹ Multiple in silico tools predict no deleterious effect: SpliceAI max delta=0.0, REVEL=0.328, BayesDel=-0.085, meeting BP4 at supporting benign level.² ClinVar reports the variant as Uncertain Significance by multiple clinical laboratories (Variation ID 458014) with no expert panel classification.³ The variant does not reside in a known functional domain or mutational hotspot. No same-residue pathogenic comparator (PM5) or de novo evidence (PS2/PM6) was identified. Overall, the available evidence is limited to population frequency data (PM2_supporting) and computational predictions (BP4_supporting_benign), which offset each other. The variant remains a Variant of Uncertain Significance.

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗

2 spliceai ↗revelbayesdel

3 clinvar ↗

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

Population frequency

Overall AF

9 / 1,613,804

0.00056%

Highest · European (Finnish)

0.0031%

Homozygotes

0

grpmax FAF

0.00025%

Allele frequency by ancestry — gnomAD v4.1

observed in 2 of 9 groups

Ancestry	Allele count	Frequency	Homozygotes
European (Finnish)	2 / 63,958	0.0031%	0
European (non-Finnish)	7 / 1,179,868	0.00059%	0
Admixed American	0 / 59,988	—	—
Amish	0 / 910	—	—
East Asian	0 / 44,860	—	—
Middle Eastern	0 / 6,062	—	—
South Asian	0 / 91,068	—	—
Ashkenazi Jewish	0 / 29,600	—	—
African/African American	0 / 75,004	—	—

“

This variant is present in gnomAD v4.1 (AF= 5.57689e-06; MAF= 0.00056%, 9/1613804 alleles, homozygotes = 0) and has highest observed frequency in the European (Finnish) population (AF= 3.12705e-05; MAF= 0.00313%, 2/63958 alleles, homozygotes = 0); grpmax FAF= 2.47e-06.

“

Absent from gnomAD v2.1.

“

This variant is absent from gnomAD-Canada.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 458014)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.328. BayesDel score = -0.0851511.

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 ↗

Literature · 16 PMIDs triaged · 8 high-priority

16papers screened

Papers triaged by theme: functional/splicing/segregation/case_observation. high_priority_papers include abstract snippets. Use these to support PS3/BS3/PS4/PP1/PP3/PP5.

25645574 ↗ splicing rna

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

This guideline presents recommendations for the management of patients with hereditary gastrointestinal cancer syndromes. The initial assessment is the collection of a family history of cancers and premalignant gastrointestinal conditions and should provide enough information to develop a preliminary determination of the risk of a familial predisposition to cancer. Age at diagnosis and lineage (ma

BP7PP3PP5PS4PVS1

25741868 ↗ functional

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.

The American College of Medical Genetics and Genomics (ACMG) previously developed guidance for the interpretation of sequence variants.(1) In the past decade, sequencing technology has evolved rapidly with the advent of high-throughput next-generation sequencing. By adopting and leveraging next-generation sequencing, clinical laboratories are now performing an ever-increasing catalogue of genetic

BS3PP5PS3PS4

31672839 ↗ splicing rna

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

The International Cancer of the Pancreas Screening Consortium met in 2018 to update its consensus recommendations for the management of individuals with increased risk of pancreatic cancer based on family history or germline mutation status (high-risk individuals). A modified Delphi approach was employed to reach consensus among a multidisciplinary group of experts who voted on consensus statement

BP7PP3PP5PS4PVS1

15604628 ↗ case observation

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

These cancer genetic counseling recommendations describe the medical, psychosocial, and ethical ramifications of identifying at-risk individuals through cancer risk assessment with or without genetic testing. They were developed by members of the Practice Issues Subcommittee of the National Society of Genetic Counselors Cancer Genetic Counseling Special Interest Group. The information contained in

PP5PS4

20301443 ↗ case observation

Untitled reference

PP5PS4

23788249 ↗ case observation

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

In clinical exome and genome sequencing, there is a potential for the recognition and reporting of incidental or secondary findings unrelated to the indication for ordering the sequencing but of medical value for patient care. The American College of Medical Genetics and Genomics (ACMG) recently published a policy statement on clinical sequencing that emphasized the importance of alerting the pati

PP5PS4

25356965 ↗ case observation

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

These recommendations are designed primarily as an educational resource for medical geneticists and other health-care providers to help them provide quality medical genetics services. Adherence to these recommendations does not necessarily ensure a successful medical outcome. These recommendations should not be considered inclusive of all proper procedures and tests or exclusive of other procedure

PP5PS4

25394175 ↗ case observation

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.

The practice guidelines of the American College of Medical Genetics and Genomics (ACMG) and the National Society of Genetic Counselors (NSGC) are developed by members of the ACMG and NSGC to assist medical geneticists, genetic counselors, and other health-care providers in making decisions about appropriate management of genetic concerns, including access to and/or delivery of services. Each pract

PP5PS4

28492532 ↗ background review

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

PP5PS4

Sources & reference links

7Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

SpliceAI

OncoKB

COSMIC

Cancer hotspots