Classification rationale

PM2PP3 VUS

CDKN2A c.221A>T missense · exon 2

PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. PP3 (Moderate): REVEL 0.903 meets the calibrated >=0.773 pathogenic threshold (PMID 36413997). Overall classification: VUS, per generic ACMG/AMP 2015 combination rules (PMID 25741868) with only supporting-to-moderate evidence.

PM2 + PP3 → VUS

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

CDKN2A NM_000077.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 22 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 · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.

Independent GRCh37 and GRCh38 gnomAD queries for the normalized variant returned absent.The gnomAD-Canada v1.0 query also returned absent.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP3 moderate Pathogenic

Met (Moderate): REVEL 0.903 meets the calibrated >=0.773 pathogenic threshold; SpliceAI predicts no splice impact (max delta 0.00).

compact_evidence.revel.score = 0.903, found=true (local REVEL v1.3 predictor lookup, source_registry key 'revel').REVEL >=0.773 meets the ClinGen SVI-recommended PP3_Moderate threshold from Pejaver et al. 2022, 'Calibration of computational tools for missense variant pathogenicity classification and ClinGen recommendation for PP3/BP4 criteria' (PMID 36413997); score 0.903 does not reach the >=0.932 PP3_Strong threshold from the same publication.compact_evidence.spliceai.evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).' -- confirms the splice-impact sub-path is uninformative for this missense variant and is not being double-counted toward PP3.

spliceai ↗

Assessed · not applied · 7 not met · 15 not assessed

Pathogenic

PS1 Not assessed: no established pathogenic variant causing the identical p.Asp74Val amino acid change via a different nucleotide substitution was identified.

PS2 Not assessed: no confirmed de novo occurrence is documented for this variant.

PS3 Not assessed: no well-established functional assay data for p.Asp74Val were available.

PS4 Not assessed: no case-control or cohort enrichment data for p.Asp74Val were available.

PM1 Not assessed: no citable evidence established position 74 as a mutational hotspot or critical functional-domain residue.

PM3 Not assessed: no affected proband with a second pathogenic CDKN2A variant or recessive disease context was documented.

PM5 Not assessed: no pathogenic missense variant at the same codon 74 was identified for comparison.

PM6 Not assessed: no presumed de novo occurrence without confirmed parentage is documented.

PP1 Not assessed: no informative relatives, pedigree, or segregation data were available.

PP2 Not assessed: no missense-constraint metric was available to establish a low benign missense rate in CDKN2A.

PP4 Not assessed: no individual-level phenotype or family-history data were provided.

PP5 Not met: no ClinVar expert-panel pathogenic classification exists for this variant.

Benign

BA1 Not met: variant is absent from gnomAD, so the stand-alone high-frequency benign threshold is not reached.

BS1 Not met: no population allele frequency was observed, so the disease-compatible BS1 threshold is not exceeded.

BS2 Not met: no healthy adult homozygotes or other population observations support BS2.

BS3 Not assessed: no well-established assay demonstrating normal p.Asp74Val function was available.

BS4 Not assessed: no informative non-segregation observation was available.

BP1 Not met: OncoKB curates p.Asp74Val as 'Likely Oncogenic', indicating missense is not inherently benign in CDKN2A.

BP2 Not assessed: no observation of the variant in cis or trans with a pathogenic variant was available.

BP4 Not met: REVEL 0.903 falls in the pathogenic-supporting range (>=0.773), not the benign range.

BP5 Not assessed: no affected individual with an independently established alternative molecular diagnosis was documented.

BP6 Not met: no ClinVar expert-panel benign classification exists for this variant.

N/A · 4 PVS1 · PM4 · BP3 · 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

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 820911)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.903. BayesDel score = 0.514125.

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 Hotspot

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58689077, 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 · 4 PMIDs not cited in assessment

25353071 ↗ Efficacy and tolerability of vemurafenib in patients with BRAF(V600E) -positive papillary thyroid cancer: M.D. Anderson Cancer Center off label experience. 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

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

26389333 ↗ Genetics of Skin Cancer (PDQ®): Health Professional Version. CLINVAR