NM_001195132.1:c.124A>C

CDKN2A · NP_001182061.1:p.(Asn42His) · NM_001195132.1

GRCh37: chr9:21974703 T>G · GRCh38: chr9:21974704 T>G

Gene: CDKN2A Transcript: NM_001195132.1

Final call

VUS

PM1 moderate PM2 moderate BP4 supporting benign

Variant details

Gene

CDKN2A

Transcript

NM_001195132.1

Protein

NP_001182061.1:p.(Asn42His)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

PM1 is met at moderate strength: the variant (p.Asn42His) lies within a statistically significant mutational hotspot in CDKN2A, a critical functional domain for CDK4/CDK6 binding.

PM2 is met at moderate strength: NM_001195132.1:c.124A>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada (allele frequency < 0.1%).

BP4 is met at supporting benign strength: multiple computational tools (SpliceAI max delta 0.03, BayesDel -0.0537, REVEL 0.441) do not support a deleterious effect on the gene product.

PVS1 is not met: the variant is a missense substitution (p.Asn42His), not a null variant eligible for PVS1 under the ClinGen SVI framework (PMC6185798).

PS1, PS2, PS3, PS4, PM6, PP1, PP2, PP3, PP4, PP5, BA1, BS1, BS2, BS3, BS4, and BP2 are not met: no variant-specific evidence meeting these criteria was identified in the literature, ClinVar, or population databases.

Overall classification: Uncertain Significance (VUS). Two moderate pathogenic criteria (PM1, PM2) and one supporting benign criterion (BP4) are met. This does not reach the Likely Pathogenic threshold (requires ≥3 moderate; or ≥2 moderate + ≥2 supporting; or ≥1 strong + ≥1 moderate) under generic ACMG/AMP 2015 combination rules (PMID:25741868).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, 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	Not met	This is a missense variant (NM_001195132.1:c.124A>C, p.Asn42His). The variant does not fall into the default generic PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Per the ClinGen SVI PVS1 decision tree (PMC6185798), this variant is not eligible for PVS1 application.	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No pathogenic or likely pathogenic variant at the same residue (p.Asn42) with a different nucleotide change has been identified. No same-residue comparators were recovered from ClinVar or the PM5 candidate search.	pm5_candidates clinvar
PS2	Not met	No de novo occurrence has been reported for NM_001195132.1:c.124A>C. No paper in the literature packet describes a de novo observation of this variant.
PS3	Not met	No well-established in vitro or in vivo functional studies have been identified for NM_001195132.1:c.124A>C (p.Asn42His). OncoKB classifies the variant as Likely Oncogenic in a somatic context, but this is a curated literature-based label, not primary functional evidence meeting PS3 standards for germline interpretation.	oncokb
PS4	Not met	The prevalence of this variant in affected individuals has not been shown to be significantly increased compared to controls. The variant is absent from population databases, and no multiple unrelated probands with the same phenotype have been reported. The single ClinVar submission is from Ambry Genetics (VUS, single submitter) and does not provide case-level phenotype data. The one paper (PMID:25394175) is a practice guideline and contains no patient-specific variant data.	clinvar gnomad_v2 gnomad_v4
PS5	N/A	PS5 is not a standard ACMG/AMP 2015 criterion and no validated clinical framework in use for this case supports PS5 application.
PM1	Met	This variant (p.Asn42His) is located at a residue within a statistically significant mutational hotspot as identified by CancerHotspots.org. Codon 42 lies within the first ankyrin repeat domain of p16INK4A, a critical functional domain for CDK4/CDK6 binding and cell cycle regulation.
PM2	Met	NM_001195132.1:c.124A>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). This meets the PM2 threshold of allele frequency < 0.1% in population databases.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	N/A	PM3 applies to variants identified in trans with a pathogenic variant in recessive disorders. CDKN2A-associated disease (familial melanoma) is autosomal dominant; PM3 is not applicable.
PM4	N/A	PM4 applies to protein length changes from non-repeat in-frame deletions/insertions or stop-loss variants. This is a missense substitution (p.Asn42His).
PM5	N/A	No pathogenic or likely pathogenic variant at the same residue (Asn42) with a different amino acid change has been identified in ClinVar. The PM5 candidate search returned zero same-residue comparators.	pm5_candidates
PM6	Not met	No de novo observation of NM_001195132.1:c.124A>C has been reported with confirmed maternity and paternity. No paper describes de novo occurrence of this variant.
PP1	Not met	No segregation data are available for NM_001195132.1:c.124A>C. No family studies have been reported.
PP2	Not met	PP2 requires a missense Z-score > 3.09 or equivalent evidence that the gene has a low rate of benign missense variation. HCI prior data is not available for CDKN2A, and no ClinGen-calibrated missense constraint metric was retrieved for this gene. Without quantitative constraint data, PP2 cannot be applied.
PP3	Not met	Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.441 (indeterminate, below the typical damaging threshold of >0.75). BayesDel score is -0.0537 (negative, favors benign). SpliceAI predicts no significant splice impact (max delta score = 0.03).	revel bayesdel spliceai
PP4	Not met	No specific phenotype or clinical presentation has been reported for patients carrying NM_001195132.1:c.124A>C. The variant's phenotype specificity cannot be assessed without case-level clinical data.
PP5	Not met	No reputable source has classified NM_001195132.1:c.124A>C as pathogenic or likely pathogenic. The sole ClinVar entry (Variation ID 1795891) is classified as Uncertain Significance by Ambry Genetics (single submitter) and is not an exact match for this transcript — it corresponds to NM_000077.5:c.277A>C (p.Thr93Pro), a different CDKN2A isoform. The one associated paper (PMID:25394175) is an ACMG/NSGC practice guideline that does not mention this variant.	clinvar
BA1	Not met	NM_001195132.1:c.124A>C is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada). The BA1 threshold of allele frequency > 1% is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	NM_001195132.1:c.124A>C is absent from all population databases. The BS1 threshold of allele frequency > 0.3% is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No observation of NM_001195132.1:c.124A>C in a healthy adult individual has been reported. The variant is absent from gnomAD; no homozygous or heterozygous observations in unaffected controls are available.
BS3	Not met	No well-established in vitro or in vivo functional studies have demonstrated that NM_001195132.1:c.124A>C (p.Asn42His) has no damaging effect on protein function or splicing.
BS4	Not met	No segregation data are available to demonstrate lack of cosegregation with disease. No family studies have been reported for this variant.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants are known to cause disease. CDKN2A has both missense and truncating variants as established disease mechanisms in familial melanoma, so BP1 is not applicable.	pvs1_gene_context
BP2	Not met	No observation of NM_001195132.1:c.124A>C in trans with a known pathogenic CDKN2A variant has been reported. No phase data are available.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. This is a missense substitution.
BP4	Met	Multiple lines of computational evidence suggest no significant impact on the gene product. SpliceAI predicts no splicing alteration (max delta = 0.03). BayesDel score is -0.0537, within the benign range. REVEL score is 0.441, in the indeterminate range and below the typical pathogenic threshold of 0.75. Together, these in silico predictions do not support a damaging effect.	spliceai revel bayesdel
BP5	N/A	BP5 requires that the variant be found in a case with an alternate molecular basis for disease. No such evidence is available and this criterion is rarely applicable in practice for a variant with no case-level data.
BP6	N/A	No reputable source has classified NM_001195132.1:c.124A>C as benign or likely benign. The sole ClinVar submission is VUS, and it is not an exact match for this transcript.
BP7	N/A	BP7 applies to synonymous (silent) variants for which splicing algorithms predict no impact. NM_001195132.1:c.124A>C is a missense variant (p.Asn42His), not a synonymous variant.

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