CDKN2A

Final classification

VUS

CDKN2A c.124A>C · p.Asn42His

CDKN2A

PM1 is met at moderate strength: the variant (p.Asn42His) lies within a statistically significant mutational hotspot in CDKN2A, a critical functional domain for CDK4/CDK6 binding.

Gene

CDKN2A

Transcript

NM_001195132.1

HGVS · transcript:coding

NM_001195132.1:c.124A>C

Consequence

N/A

GRCh38

chr9:21974704 T>G

GRCh37

chr9:21974703 T>G

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, BP4 supporting benign; combination = 2 moderate + 1 supporting benign, which maps to VUS. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM1 moderate, PM2 moderate, BP4 supporting benign; combination = 2 moderate + 1 supporting benign, which maps to VUS.

Classification rationale

PM1PM2 BP4 VUS

CDKN2A c.124A>C

PM1 is met at moderate strength: the variant (p.Asn42His) lies within a statistically significant mutational hotspot in CDKN2A, a critical functional domain for CDK4/CDK6 binding. PM2 is met at moderate strength: NM_001195132.1:c.124A>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency < 0.1%).¹ BP4 is met at supporting benign strength: multiple computational tools (SpliceAI max delta 0.03, BayesDel -0.0537, REVEL 0.441) do not support a deleterious effect on the gene product.² PVS1 is not met: the variant is a missense substitution (p.Asn42His), not a null variant eligible for PVS1 under the ClinGen SVI framework (PMC6185798).³ PS1, PS2, PS3, PS4, PM6, PP1, PP2, PP3, PP4, PP5, BA1, BS1, BS2, BS3, BS4, and BP2 are not met: no variant-specific evidence meeting these criteria was identified in the literature, ClinVar, or population databases. Overall classification: Uncertain Significance (VUS). Two moderate pathogenic criteria (PM1, PM2) and one supporting benign criterion (BP4) are met. This does not reach the Likely Pathogenic threshold (requires ≥3 moderate; or ≥2 moderate + ≥2 supporting; or ≥1 strong + ≥1 moderate) under generic ACMG/AMP 2015 combination rules (PMID:25741868).⁴

PM1 + PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 spliceai ↗revelbayesdel

3 pvs1_generic_framework ↗pvs1_variant_assessment

4 generic_acmg_combination_rules

Gene diagram · NM_001195132.1 · variants mapped to exon structure

CDKN2A NM_001195132.1

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 17 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PM1 moderate Pathogenic

This variant (p.Asn42His) is located at a residue within a statistically significant mutational hotspot as identified by CancerHotspots.org. Codon 42 lies within the first ankyrin repeat domain of p16INK4A, a critical functional domain for CDK4/CDK6 binding and cell cycle regulation.

CancerHotspots.org identifies codon 42 as a statistically significant hotspot.Residue Asn42 lies within the ankyrin repeat domain of p16INK4Awhich mediates CDK4/CDK6 interaction.

✓

PM2 moderate Pathogenic

NM_001195132.1:c.124A>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). This meets the PM2 threshold of allele frequency < 0.1% in population databases.

Absent from gnomAD v2.1.Absent from gnomAD v4.1.Absent from gnomAD-Canada v1.0.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence suggest no significant impact on the gene product. SpliceAI predicts no splicing alteration (max delta = 0.03). BayesDel score is -0.0537, within the benign range. REVEL score is 0.441, in the indeterminate range and below the typical pathogenic threshold of 0.75. Together, these in silico predictions do not support a damaging effect.

SpliceAI max delta: 0.03 (no splicing impact).BayesDel: -0.0537 (benign).REVEL: 0.441 (indeterminate

spliceai ↗

Assessed · not applied

Pathogenic

PVS1 This is a missense variant (NM_001195132.1:c.124A>C, p.Asn42His).

PS1 No pathogenic or likely pathogenic variant at the same residue (p.Asn42) with a different nucleotide change has been identified.

PS2 No de novo occurrence has been reported for NM_001195132.1:c.124A>C.

PS3 No well-established in vitro or in vivo functional studies have been identified for NM_001195132.1:c.124A>C (p.Asn42His).

PS4 The prevalence of this variant in affected individuals has not been shown to be significantly increased compared to controls.

PM6 No de novo observation of NM_001195132.1:c.124A>C has been reported with confirmed maternity and paternity.

PP1 No segregation data are available for NM_001195132.1:c.124A>C.

PP2 PP2 requires a missense Z-score > 3.09 or equivalent evidence that the gene has a low rate of benign missense variation.

PP3 Multiple lines of in silico evidence do not support a deleterious effect.

PP4 No specific phenotype or clinical presentation has been reported for patients carrying NM_001195132.1:c.124A>C.

PP5 No reputable source has classified NM_001195132.1:c.124A>C as pathogenic or likely pathogenic.

Benign

BA1 NM_001195132.1:c.124A>C is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada).

BS1 NM_001195132.1:c.124A>C is absent from all population databases.

BS2 No observation of NM_001195132.1:c.124A>C in a healthy adult individual has been reported.

BS3 No well-established in vitro or in vivo functional studies have demonstrated that NM_001195132.1:c.124A>C (p.Asn42His) has no damaging effect on protein function or splicing.

BS4 No segregation data are available to demonstrate lack of cosegregation with disease.

BP2 No observation of NM_001195132.1:c.124A>C in trans with a known pathogenic CDKN2A variant has been reported.

N/A · 8 PM3 · PM4 · PM5 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

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

Error retrieving ClinVar entry.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.441. BayesDel score = -0.0537043.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; 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; COSV58703253, n = 4 times).

Hotspots

This variant lies 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 · 1 PMID not cited in assessment

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