LYFE Sciences · Project HERA
Variant Interpretation · Classification Report
Generated: 2026-08-19
Case ID: NM_000077.4_c.221A_T_20260819_194114
Framework: ACMG/AMP 2015
Variant classification summary

NM_000077.4:c.221A>T

CDKN2A  · NP_000068.1:p.(Asp74Val)  · NM_000077.4
GRCh37: chr9:21971137 T>A  ·  GRCh38: chr9:21971138 T>A
Gene: CDKN2A Transcript: NM_000077.4
Final call
VUS
PM2 supporting PP3 moderate
All criteria require review: For research and educational purposes only.
Variant details
Gene
CDKN2A
Transcript
NM_000077.4
Protein
NP_000068.1:p.(Asp74Val)
gnomAD AF
ClinVar
Uncertain significance
OncoKB
Likely Oncogenic
Classification rationale
Interpretation summary
Generated evidence synthesis
1
PM2 (Supporting): variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.
2
PP3 (Moderate): REVEL 0.903 meets the calibrated >=0.773 pathogenic threshold (PMID 36413997).
3
Overall classification: VUS, per generic ACMG/AMP 2015 combination rules (PMID 25741868) with only supporting-to-moderate evidence.
Final determination: 1 moderate + 1 supporting does not meet any P/LP/B/LB threshold under generic ACMG/AMP 2015 rules, defaulting to VUS.
Criteria assessment
ACMG/AMP criteria review
Criteria shown when status is available
All criteria require review: For research and educational purposes only.
Criterion Status Rationale Evidence used
PVS1 N/A Not applicable: missense substitution p.(Asp74Val) does not trigger a null-variant mechanism such as nonsense-mediated decay.
pvs1_generic_framework generic_acmg_combination_rules
PS1 Not assessed Not assessed: no established pathogenic variant causing the identical p.Asp74Val amino acid change via a different nucleotide substitution was identified.
pm5_candidates
PS2 Not assessed Not assessed: no confirmed de novo occurrence is documented for this variant.
clinvar
PS3 Not assessed Not assessed: no well-established functional assay data for p.Asp74Val were available.
PS4 Not assessed Not assessed: no case-control or cohort enrichment data for p.Asp74Val were available.
clinvar
PM1 Not assessed Not assessed: no citable evidence established position 74 as a mutational hotspot or critical functional-domain residue.
oncokb
PM2 Met Met (Supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.
gnomad_v2 gnomad_v4 gnomad_canada
PM3 Not assessed Not assessed: no affected proband with a second pathogenic CDKN2A variant or recessive disease context was documented.
final_classification_framework clinvar
PM4 N/A Not applicable: missense substitution causes no change in protein length.
pvs1_generic_framework generic_acmg_combination_rules
PM5 Not assessed Not assessed: no pathogenic missense variant at the same codon 74 was identified for comparison.
pm5_candidates
PM6 Not assessed Not assessed: no presumed de novo occurrence without confirmed parentage is documented.
clinvar
PP1 Not assessed Not assessed: no informative relatives, pedigree, or segregation data were available.
clinvar
PP2 Not assessed Not assessed: no missense-constraint metric was available to establish a low benign missense rate in CDKN2A.
PP3 Met Met (Moderate): REVEL 0.903 meets the calibrated >=0.773 pathogenic threshold; SpliceAI predicts no splice impact (max delta 0.00).
revel spliceai
PP4 Not assessed Not assessed: no individual-level phenotype or family-history data were provided.
PP5 Not met Not met: no ClinVar expert-panel pathogenic classification exists for this variant.
clinvar
BA1 Not met Not met: variant is absent from gnomAD, so the stand-alone high-frequency benign threshold is not reached.
gnomad_v2 gnomad_v4 gnomad_canada
BS1 Not met Not met: no population allele frequency was observed, so the disease-compatible BS1 threshold is not exceeded.
gnomad_v2 gnomad_v4 gnomad_canada
BS2 Not met Not met: no healthy adult homozygotes or other population observations support BS2.
gnomad_v2 gnomad_v4 gnomad_canada
BS3 Not assessed Not assessed: no well-established assay demonstrating normal p.Asp74Val function was available.
BS4 Not assessed Not assessed: no informative non-segregation observation was available.
clinvar
BP1 Not met Not met: OncoKB curates p.Asp74Val as 'Likely Oncogenic', indicating missense is not inherently benign in CDKN2A.
oncokb pvs1_gene_context
BP2 Not assessed Not assessed: no observation of the variant in cis or trans with a pathogenic variant was available.
final_classification_framework clinvar
BP3 N/A Not applicable: missense substitution is not an in-frame insertion/deletion in a repetitive region.
pvs1_generic_framework generic_acmg_combination_rules
BP4 Not met Not met: REVEL 0.903 falls in the pathogenic-supporting range (>=0.773), not the benign range.
revel spliceai
BP5 Not assessed Not assessed: no affected individual with an independently established alternative molecular diagnosis was documented.
BP6 Not met Not met: no ClinVar expert-panel benign classification exists for this variant.
clinvar
BP7 N/A Not applicable: applies to synonymous variants; p.Asp74Val alters the encoded protein.
generic_acmg_combination_rules
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