Classification rationale

PVS1PM2 BP4 Likely Pathogenic

CDKN2A c.307_308insT frameshift · exon 2

PVS1 (Very Strong): frameshift predicted to trigger nonsense-mediated decay, a loss-of-function mechanism established in CDKN2A. PM2 (Moderate): variant absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases. BP4 (Supporting): no splice-altering effect predicted (SpliceAI/Pangolin max delta 0.00); applies to splicing only. Combining PVS1 (very strong) plus PM2 (moderate) under generic ACMG/AMP 2015 rules yields Likely Pathogenic.

PVS1 + PM2 + BP4 → Likely Pathogenic

Gene diagram · NM_000077.4 · variants mapped to exon structure

CDKN2A NM_000077.4

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

✓

PVS1 very strong Pathogenic

Met at very strong: the frameshift creates a premature stop 17 codons after residue 103, predicted to trigger nonsense-mediated decay.

pvs1_variant_assessment.json classifies the variant consequence as frameshift, transcript NM_000077.4:c.307_308insT, protein NP_000068.1:p.(Arg103LeufsTer17), and flags apply_generic_pvs1_framework=true with suggested_default_strength=PVS1, framework PMC6185798.pvs1_gene_context.json establishes pvs1_gene_gate=eligible: germline loss-of-function is a supported CDKN2A disease mechanism (lof_mechanism_supported=true), based on targeted germline literature review of CDKN2A-related melanoma predisposition; no official CSPEC/VCEP PVS1 framework exists for this gene so the generic fallback per PMC6185798 was directed.Applying the ClinGen SVI PVS1 decision tree (PMC6185798) to a frameshift variant: the resulting premature stop codon (p.Arg103LeufsTer17, terminating around codon 119 of the 156-aa p16INK4a protein) falls within exon 2, which is not the terminal exon and is well upstream of the final exon-exon junction, predicting NMD and truncation/loss of the C-terminal ankyrin-repeat region required for CDK4/CDK6 inhibitory function.

pvs1_generic_framework ↗

✓

PM2 moderate Pathogenic

Met at moderate: the variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada population databases.

The evidence bundle reports this exact normalized allele absent from gnomAD v2.1 (GRCh37 9-21971050-C-CA), gnomAD v4.1 (GRCh38 9-21971051-C-CA), and gnomAD-Canada v1.0.No CDKN2A VCEP/CSPEC population-frequency framework was available in the case materials; generic ACMG/AMP is the designated fallback.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting review Benign

Met at supporting: SpliceAI/Pangolin max delta score 0.00, below the ~0.1 threshold, so no splice-altering effect is predicted. Flagged for human review: this covers splicing only and should not be read as broad benign support.

prefetch.json/evidence.json: SpliceAI max_delta_score = 0.00 (pangolin_SG 0.003, pangolin_SL -0.068) for NM_000077.4:c.307_308insT; evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).'Jaganathan et al. 2019 (PMID 30661751) established the SpliceAI delta-score framework; scores near 0.00, well under the ~0.1 low-confidence threshold, are conventionally used as benign-supporting (BP4) evidence against a splice-altering effect.prefetch.json: revel and bayesdel both skipped ('not snv or no coords'), confirming missense in-silico predictors are not_available for this frameshift insertion and cannot independently drive BP4.

spliceai ↗

Assessed · not applied · 6 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no parental genotypes, parentage confirmation, or proband phenotype were available to test a de novo occurrence.

PS3 Not assessed: no functional assay evidence specific to this exact variant was available.

PS4 Not assessed: no variant-specific case series or case-control data were available.

PM3 Not assessed: no evidence places this variant in trans with a pathogenic variant under a recessive inheritance model.

PM6 Not assessed: no parental testing or proband phenotype was provided to confirm a de novo event without confirmed parentage.

PP1 Not assessed: no pedigree or relative genotype-phenotype data were available to evaluate segregation.

PP3 Not met: SpliceAI max delta score 0.00, far below splice-altering thresholds, and no missense score applies to a frameshift.

PP4 Not assessed: no proband phenotype or personal/family cancer history was provided.

PP5 Not met: the exact variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.

Benign

BA1 Not met: absent from gnomAD v2.1, v4.1, and gnomAD-Canada, far below the standalone high-frequency threshold.

BS1 Not met: absent from population databases, so not more frequent than expected for a CDKN2A-related disorder.

BS2 Not met: no carriers observed in healthy individuals; the variant is absent from all population datasets.

BS3 Not assessed: no variant-specific assay demonstrating normal protein function was available.

BS4 Not assessed: no genotype-phenotype data on affected relatives or evaluated unaffected carriers were available.

BP2 Not assessed: no data document this variant in cis or in trans with another pathogenic or likely pathogenic variant.

BP5 Not assessed: no affected individual, phenotype attribution, or alternate molecular diagnosis was provided.

BP6 Not met: the exact variant is absent from ClinVar, so no expert-panel benign assertion exists.

N/A · 8 PS1 · PM1 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency · supports pathogenic

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

This variant is absent from ClinVar.

ClinVar ↗

In silico

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

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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 · 2 PMIDs not cited in assessment

8603820 ↗ Cancer-associated mis-sense and deletion mutations impair p16INK4 CDK inhibitory activity. ONCOKB

8668202 ↗ Temperature-sensitive mutants of p16CDKN2 associated with familial melanoma. ONCOKB