Variant classification summary

NM_000077.4:c.76G>C

CDKN2A · NP_000068.1:p.(Glu26Gln) · NM_000077.4

GRCh37: chr9:21974751 C>G · GRCh38: chr9:21974752 C>G

Gene: CDKN2A Transcript: NM_000077.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

CDKN2A

Transcript

NM_000077.4

Protein

NP_000068.1:p.(Glu26Gln)

gnomAD AF

1.2414556812736342e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely rare in population databases, with gnomAD v4.1 allele frequency 0.000124% (2/1,611,012 alleles).

2

BP4 (Supporting): SpliceAI max delta 0.006 and REVEL 0.155, both below calibrated benign-supporting thresholds.

3

Overall classification: VUS — PM2 (Supporting) plus BP4 (Supporting) does not reach any ACMG/AMP 2015 combination threshold.

Final determination: PM2(supporting)+BP4(supporting) meets no P/LP/B/LB combination rule → 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: this is a missense change (p.Glu26Gln), so no null-variant mechanism such as nonsense-mediated decay is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no other reported variant producing the same amino-acid change p.Glu26Gln was identified.
PS2	Not assessed	Not assessed: no de novo occurrence with parental testing was documented.
PS3	Not assessed	Not assessed: no validated functional assay of this variant was identified; the ClinVar submitter confirms functional studies have not been reported.
PS4	Not assessed	Not assessed: no case-control or enrichment data for this exact variant were available.	generic_acmg_combination_rules
PM1	Not assessed	Not assessed: the variant is not in a statistical mutational hotspot, and no domain/structural source was available to evaluate residue 26.
PM2	Met	Met (Supporting): extremely rare in population databases, with gnomAD v4.1 allele frequency 0.000124% (2/1,611,012 alleles).	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: PM3 applies to recessive disease, and this is a dominant cancer-predisposition context with no biallelic evidence.	clinvar
PM4	N/A	Not applicable: missense change does not alter protein length, so the length-change criterion has nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense at the same residue (position 26) was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no de novo occurrence with unconfirmed parentage was reported.
PP1	Not assessed	Not assessed: no family segregation or pedigree data were available.
PP2	Not assessed	Not assessed: missense is a recognized disease mechanism in CDKN2A, but no gene-level missense constraint metric was available to verify the threshold.
PP3	Not met	Not met: REVEL 0.155 and SpliceAI max delta 0.006 are far below any pathogenic-supporting threshold.	spliceai revel
PP4	Not assessed	Not assessed: no proband phenotype or differential assessment was provided.	generic_acmg_combination_rules
PP5	Not met	Not met: all three ClinVar submissions classify this variant as uncertain significance, with no expert-panel pathogenic assertion.	clinvar
BA1	Not met	Not met: highest population frequency is 0.00657% (gnomAD v2.1 South Asian), far below a stand-alone benign threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: highest observed frequency 0.00657% is too low to exceed the benign expectation for this condition.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: population records lack unaffected-carrier adult phenotype data.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional study of this variant showing normal function was identified.
BS4	Not assessed	Not assessed: no informative non-segregation data (affected non-carriers or unaffected carriers) were available.
BP1	Not met	Not met: CDKN2A missense variants are a recognized disease mechanism, so the truncating-only-gene premise does not apply.
BP2	Not assessed	Not assessed: no phase data or observation of this variant alongside a pathogenic variant in the same individual.	clinvar
BP3	N/A	Not applicable: missense change does not alter protein length within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Supporting): SpliceAI max delta 0.006 and REVEL 0.155, both below calibrated benign-supporting thresholds.	spliceai revel
BP5	Not assessed	Not assessed: no affected individual or alternate molecular diagnosis was provided.	generic_acmg_combination_rules
BP6	Not met	Not met: no expert-panel benign assertion exists; ClinVar has only uncertain-significance laboratory submissions.	clinvar
BP7	N/A	Not applicable: criterion applies to synonymous variants, and this missense change alters the protein sequence.	generic_acmg_combination_rules

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