Classification rationale

PM2PP3 VUS

CDKN2A c.253G>T missense · exon 2

PM2 (Moderate): ultra-rare population frequency (gnomAD v4.1 AF 3.12e-06, 0 homozygotes), more than 10-fold below the 0.1% rarity threshold. PP3 (Supporting): REVEL 0.796 predicts a damaging effect, above the 0.750 missense threshold. Synthesis: PM2 (moderate) plus PP3 (supporting) satisfies no pathogenic or benign rule in the generic ACMG/AMP 2015 framework, so the variant is classified as a Variant of Uncertain Significance.

PM2 + PP3 → VUS

Gene diagram · NM_000077.5 · variants mapped to exon structure

CDKN2A NM_000077.5

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 20 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 moderate Pathogenic

Met (moderate): ultra-rare population frequency, gnomAD v4.1 allele frequency 3.12e-06 with 0 homozygotes, more than 10-fold below the 0.1% rarity threshold.

gnomAD v4.1: total AF 3.12e-06 (0.00031%; 5/1,604,348 joint exome+genome alleles), 0 homozygotes, grpmax FAF 1.77e-05 (0.0018%); distribution limited to East Asian (3), African/African American (1), and 'remaining' (1) with 0 alleles in >1.5 million European/South Asian/other chromosomes.gnomAD v2.1: total AF 4.32e-06 (0.00043%; 1/231,476 exome alleles), 0 homozygotes.Absent from gnomAD-Canada v1.0 (HostSeq genomes), an independent concordant observation of absence/ultra-rarity.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗PMID:25741868 ↗

PP3 supporting Pathogenic

Met (supporting): REVEL score 0.796, above the 0.750 threshold predicting a damaging effect.

Governing framework: no ClinGen CSPEC for CDKN2A and no gene-specific VCEP materials retrieved (case_summary framework_mode = generic_acmg; vcep_materials.json files_found []); generic ACMG/AMP 2015 (PMID 25741868) applies, with the lab's generic in-silico operating thresholds in generic_acmg_classification_rules.md governing PP3/BP4.generic_acmg_classification_rules.md states: missense variants are evaluated with REVEL only; REVEL > 0.750 -> PP3 (supporting); REVEL < 0.250 -> BP4 (supporting); REVEL in [0.250, 0.750] -> neither met (gray zone); the SpliceAI path applies only to intronic, synonymous, or non-canonical-splice-position variants; a missense variant's own SpliceAI score does not clear its REVEL-assessed protein-level effect.Local REVEL v1.3 lookup (source_registry key 'revel') returns score 0.796 for NM_000077.5:c.253G>T (chr9:21971106 C>A; p.Ala85Ser), which is > 0.750, meeting the governing generic PP3 (supporting) threshold.

PMID:25741868 ↗

Assessed · not applied · 5 not met · 15 not assessed

Pathogenic

PS1 Not assessed: insufficient evidence was available to establish whether this exact amino-acid change has been reported as pathogenic.

PS2 Not assessed: no confirmed de novo occurrence is documented, and no parental or maternity/paternity testing was available.

PS3 Not met: no well-established functional study demonstrates a deleterious effect; submitters state functional studies have not been performed for this variant.

PS4 Not assessed: insufficient evidence of case-level enrichment among affected individuals was available.

PM1 Not assessed: insufficient evidence was available to determine whether the variant lies in a mutational hotspot.

PM5 Not assessed: insufficient evidence was available to identify a different pathogenic missense at the same residue.

PM6 Not assessed: no family-level report of a presumed de novo occurrence with unconfirmed parentage was available.

PP1 Not assessed: no co-segregation of the variant with disease in affected relatives was documented.

PP2 Not assessed: insufficient evidence was available to assess this gene's missense-variant burden.

PP4 Not assessed: insufficient phenotype-specific evidence was available.

PP5 Not assessed: insufficient evidence was available to support a benign assertion from external sources.

Benign

BA1 Not met: the highest observed allele frequency, about 0.012%, is roughly 400-fold below the 5% stand-alone benign threshold.

BS1 Not met: the maximum population allele frequency, ~0.0069%, sits well below the 0.3% benign threshold for this adult-onset dominant cancer gene.

BS3 Not met: no functional study demonstrates normal function; submitters report no functional studies have been performed for this variant.

BS4 Not assessed: no family data demonstrating non-segregation of the variant with disease were available.

BP1 Not assessed: insufficient evidence was available to evaluate whether benign missense variation is uncommon in this gene.

BP2 Not assessed: no allelic-phase data (variant in trans or in cis with a pathogenic CDKN2A variant) were available.

BP4 Not met: REVEL 0.796 is far above the 0.250 no-impact threshold, so the score supports impact rather than no impact.

BP5 Not assessed: insufficient evidence was available to identify an alternate benign missense at the same residue.

BP6 Not assessed: insufficient evidence was available from external benign classifications.

N/A · 6 PVS1 · PM3 · PM4 · BS2 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.11653e-06; MAF= 0.00031%, 5/1604348 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 6.68598e-05; MAF= 0.00669%, 3/44870 alleles, homozygotes = 0); grpmax FAF= 1.773e-05.

v2.1

This variant is present in gnomAD v2.1 (AF= 4.3201e-06; MAF= 0.00043%, 1/231476 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 6.94444e-05; MAF= 0.00694%, 1/14400 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00031% · 5 / 1,604,348
0 hom · FAF 0.0018%

East Asian 3 / 44,870	0.0067%
Remaining individuals 1 / 62,342	0.0016%
African/African American 1 / 74,908	0.0013%

+ 7 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, European (non-Finnish))

gnomAD v2.1

0.00043% · 1 / 231,476
0 hom

African/African American

1 / 14,400

0.0069%

+ 7 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals, South Asian)

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 (6 clinical laboratories). (ClinVarID = 532289)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.796. BayesDel score = 0.359592.

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. CDKN2A, which encodes both a cyclin-dependent kinase inhibitor and an MDM2 inhibitor, is altered by mutation and deletion in various cancers.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58705440, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & references.

Rule & framework references · cited for criterion definitions, not variant evidence

25741868 ↗ 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.

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

28765326 ↗ Outcome of Azacitidine Therapy in Acute Myeloid Leukemia Is not Improved by Concurrent Vorinostat Therapy but Is Predicted by a Diagnostic Molecular Signature. CLINVAR

31672839 ↗ Management of patients with increased risk for familial pancreatic cancer: updated recommendations from the International Cancer of the Pancreas Screening (CAPS) Consortium. CLINVAR

7718873 ↗ Homozygous deletions of the p16 tumor-suppressor gene are associated with lymphoid transformation of chronic myeloid leukemia. CLINVAR

16818274 ↗ The prognostic significance of CDKN2A, CDKN2B and MTAP inactivation in B-lineage acute lymphoblastic leukemia of childhood. Results of the EORTC studies 58881 and 58951. CLINVAR

18519632 ↗ Failure of CDKN2A/B (INK4A/B-ARF)-mediated tumor suppression and resistance to targeted therapy in acute lymphoblastic leukemia induced by BCR-ABL. 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