Variant classification summary

NM_001195132.1:c.341C>T

CDKN2A · NP_001182061.1:p.(Pro114Leu) · NM_001195132.1

GRCh37: chr9:21971017 G>A · GRCh38: chr9:21971018 G>A

Gene: CDKN2A Transcript: NM_001195132.1

Final call

Pathogenic

PS3 strong PM1 moderate PM2 moderate PP3 moderate PP2 supporting

Variant details

Gene

CDKN2A

Transcript

NM_001195132.1

Protein

NP_001182061.1:p.(Pro114Leu)

gnomAD AF

0.0 (v2.1)

ClinVar

Likely pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Strong): validated cell-cycle arrest assay shows p.Pro114Leu impairs cell-cycle inhibitory function, with ~100% assay PPV for pathogenicity.

2

PM1 (Moderate): p.Pro114Leu lies in the ankyrin-repeat CDK4/6-binding domain, a mutational hotspot with 92 somatic COSMIC occurrences.

3

PM2 (Moderate): the variant is absent from population databases (AC=0/AN=239,394; AF=0 in gnomAD v2.1).

4

PP3 (Moderate): REVEL 0.872 exceeds the 0.773 pathogenic-moderate threshold.

5

PP2 (Supporting): missense substitution is an established disease mechanism in CDKN2A.

6

Overall classification: Pathogenic, reached by the combination rule (1 PS) + (3 PM) with PP2 corroborating.

Final determination: Generic ACMG/AMP 2015 rule (1 PS) + (3 PM) -> Pathogenic is met by PS3(strong) plus PM1, PM2, and PP3-at-moderate, with PP2(supporting) additionally corroborating.

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 missense substitution is not in a null-variant class (nonsense, frameshift, or canonical splice-site) that PVS1 evaluates.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no alternate nucleotide change at the same codon producing the identical p.Pro114Leu change with an established pathogenic classification was identified.
PS2	Not assessed	Not assessed: no de novo observation is documented; no proband-parent trio or parental testing results were available.	clinvar
PS3	Met	Met (Strong): a validated cell-cycle arrest assay showed p.Pro114Leu causes loss of cell-cycle inhibitory function (~100% assay PPV). Flagged for human review: the original assay data trace to Greenblatt et al. 2003, which was not directly reviewed.	PMID:21462282
PS4	Not assessed	Not assessed: no case-control enrichment data were available; the single familial observation is not a case-control comparison.	PMID:21462282
PM1	Met	Met (Moderate): p.Pro114Leu lies in the ankyrin-repeat CDK4/6-binding domain, a mutational hotspot with 92 somatic COSMIC occurrences. Flagged for human review: the hotspot determination carries a parsing caveat.	gnomad_v2 gnomad_v4 clinvar PMID:17992122
PM2	Met	Met (Moderate): the variant is absent from population databases, with AF=0 and AC=0/AN=239,394 in gnomAD v2.1.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	Not applicable: PM3 is a recessive-disorder criterion, and this is a dominant cancer-predisposition context.
PM4	N/A	Not applicable: this is a missense substitution with no change in protein length, so PM4 has nothing to evaluate.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at residue Pro114 with an established pathogenic classification was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no assumed de novo observation is documented; no parental testing results were available.	clinvar
PP1	Not assessed	Not assessed: no informative co-segregation data were available; only a single carrier was reported.	PMID:21462282
PP2	Met	Met (Supporting): missense substitution is an established, recurrent disease mechanism in CDKN2A, which relies on the CDK4/6-binding domain.	clinvar PMID:21462282 PMID:17992122
PP3	Met	Met (Moderate): REVEL score 0.872 exceeds the 0.773 pathogenic-moderate threshold (ClinGen SVI calibration).	revel spliceai
PP4	Not assessed	Not assessed: no individual-level phenotype or family-history data were available to evaluate phenotype specificity.
PP5	Not met	Not met: ClinVar has no expert-panel Pathogenic or Likely pathogenic assertion for this exact variant.	clinvar
BA1	Not met	Not met: the variant is absent from population databases (AF=0 in gnomAD), so the stand-alone high-frequency threshold is not approached.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: with zero observed alleles and AF=0, the frequency cannot exceed the threshold expected for a dominant cancer-predisposition gene.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: the variant is absent rather than observed in healthy adults, and incomplete penetrance limits any BS2 inference.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not met	Not met: functional assays demonstrate a damaging loss-of-function effect, the opposite of the wild-type result BS3 requires.	PMID:21462282
BS4	Not assessed	Not assessed: no evidence of an affected relative lacking the variant or other non-segregation data was available.	PMID:21462282
BP1	Not met	Not met: missense variation is an established pathogenic mechanism in CDKN2A, so BP1's truncation-dominant premise does not hold.	clinvar PMID:21462282 PMID:17992122
BP2	Not assessed	Not assessed: no cis or trans occurrence with a pathogenic CDKN2A variant was documented.
BP3	N/A	Not applicable: BP3 concerns in-frame indels in repetitive regions, and this variant is a missense substitution.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.872 is far above the benign supporting threshold (<=0.183), arguing against a benign computational call.	revel spliceai bayesdel
BP5	Not assessed	Not assessed: no phenotype or molecular diagnostic data were available to evaluate an alternate molecular cause.
BP6	Not met	Not met: ClinVar has no expert-panel Benign or Likely benign assertion for this exact variant.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous variants, and this is a missense substitution.	generic_acmg_combination_rules

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