Variant classification summary

NM_000077.5:c.253G>T

CDKN2A · NP_000068.1:p.(Ala85Ser) · NM_000077.5

GRCh37: chr9:21971105 C>A · GRCh38: chr9:21971106 C>A

Gene: CDKN2A Transcript: NM_000077.5

Final call

VUS

PM2 moderate PP3 supporting

Variant details

Gene

CDKN2A

Transcript

NM_000077.5

Protein

NP_000068.1:p.(Ala85Ser)

gnomAD AF

3.116530827476333e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

PP3 (Supporting): REVEL 0.796 predicts a damaging effect, above the 0.750 missense threshold.

3

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.

Final determination: Generic ACMG/AMP 2015 fallback: with PM2 (moderate) and PP3 (supporting) as the only met criteria, the combination (1 moderate + 1 supporting) does not satisfy any Pathogenic, Likely Pathogenic (requires e.g. 1 moderate + 4 supporting or 2 moderate + 2 supporting), Benign (BA1 alone or 2 BS), or Likely Benign (1 BS + 1 BP or 2 BP) rule, so the variant is classified as Variant of Uncertain Significance.

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: c.253G>T is a missense change (p.Ala85Ser), not a null variant predicted to trigger nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: insufficient evidence was available to establish whether this exact amino-acid change has been reported as pathogenic.
PS2	Not assessed	Not assessed: no confirmed de novo occurrence is documented, and no parental or maternity/paternity testing was available.
PS3	Not met	Not met: no well-established functional study demonstrates a deleterious effect; submitters state functional studies have not been performed for this variant.	clinvar oncokb PMID:25741868 PMID:7718873 PMID:18519632 PMID:28765326 PMID:16818274
PS4	Not assessed	Not assessed: insufficient evidence of case-level enrichment among affected individuals was available.
PM1	Not assessed	Not assessed: insufficient evidence was available to determine whether the variant lies in a mutational hotspot.
PM2	Met	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_v2 gnomad_v4 gnomad_canada PMID:25741868
PM3	N/A	Not applicable: CDKN2A cancer susceptibility is autosomal dominant with incomplete penetrance, so the recessive in-trans criterion does not apply.	PMID:25741868 PMID:25394175 PMID:7718873 PMID:18519632 PMID:28765326 clinvar
PM4	N/A	Not applicable: this missense substitution leaves protein length unchanged, so there is no length-change effect to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: insufficient evidence was available to identify a different pathogenic missense at the same residue.
PM6	Not assessed	Not assessed: no family-level report of a presumed de novo occurrence with unconfirmed parentage was available.
PP1	Not assessed	Not assessed: no co-segregation of the variant with disease in affected relatives was documented.
PP2	Not assessed	Not assessed: insufficient evidence was available to assess this gene's missense-variant burden.
PP3	Met	Met (supporting): REVEL score 0.796, above the 0.750 threshold predicting a damaging effect.	revel generic_acmg_combination_rules PMID:25741868
PP4	Not assessed	Not assessed: insufficient phenotype-specific evidence was available.
PP5	Not assessed	Not assessed: insufficient evidence was available to support a benign assertion from external sources.
BA1	Not met	Not met: the highest observed allele frequency, about 0.012%, is roughly 400-fold below the 5% stand-alone benign threshold.	gnomad_v2 gnomad_v4 PMID:25741868
BS1	Not met	Not met: the maximum population allele frequency, ~0.0069%, sits well below the 0.3% benign threshold for this adult-onset dominant cancer gene.	gnomad_v2 gnomad_v4 PMID:25741868
BS2	N/A	Not applicable: CDKN2A disease is adult-onset with reduced penetrance, so the healthy-adult observation criterion does not apply.	gnomad_v2 gnomad_v4 PMID:25741868
BS3	Not met	Not met: no functional study demonstrates normal function; submitters report no functional studies have been performed for this variant.	clinvar oncokb PMID:25741868 PMID:7718873 PMID:18519632 PMID:28765326 PMID:16818274
BS4	Not assessed	Not assessed: no family data demonstrating non-segregation of the variant with disease were available.
BP1	Not assessed	Not assessed: insufficient evidence was available to evaluate whether benign missense variation is uncommon in this gene.
BP2	Not assessed	Not assessed: no allelic-phase data (variant in trans or in cis with a pathogenic CDKN2A variant) were available.	clinvar PMID:25741868 PMID:25394175
BP3	N/A	Not applicable: this is a missense substitution, not an in-frame insertion/deletion in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.796 is far above the 0.250 no-impact threshold, so the score supports impact rather than no impact.	revel spliceai bayesdel generic_acmg_combination_rules PMID:25741868
BP5	Not assessed	Not assessed: insufficient evidence was available to identify an alternate benign missense at the same residue.
BP6	Not assessed	Not assessed: insufficient evidence was available from external benign classifications.
BP7	N/A	Not applicable: this is a missense substitution, not a synonymous variant, so the silent-variant criterion does not apply.	generic_acmg_combination_rules

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