NM_000077.4:c.151G>T

CDKN2A · NP_000068.1:p.(Val51Phe) · NM_000077.4

GRCh37: chr9:21971207 C>A · GRCh38: chr9:21971208 C>A

Gene: CDKN2A Transcript: NM_000077.4

Final call

Likely Pathogenic

PS3 supporting PM1 moderate PM2 moderate PP2 supporting

Variant details

Gene

CDKN2A

Transcript

NM_000077.4

Protein

NP_000068.1:p.(Val51Phe)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM1 (moderate): Val51 is located in the second ankyrin repeat domain of p16INK4a, a critical functional domain essential for CDK4/CDK6 binding. Multiple pathogenic missense variants cluster in the ankyrin repeat domains and no benign variation is observed at this residue in population databases.

PM2 (moderate): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, confirming it is not a common population polymorphism.

PS3 (supporting): A functional study (PMID:10468619) demonstrated that p.Val51Phe fails to inhibit CDK4 kinase activity and is unable to induce G1 arrest in a p16-null cell line, consistent with loss of tumor suppressor function. Verification of full text is pending.

PP2 (supporting): CDKN2A is a tumor suppressor gene in which missense variants are a well-established mechanism of disease, with a low rate of benign missense variation in critical functional domains.

Under generic ACMG/AMP 2015 combination rules (PMID:25741868), two moderate criteria (PM1 + PM2) plus two supporting criteria (PS3 + PP2) meets the threshold for Likely Pathogenic (2 Moderate + 2 Supporting).

CAUTION: PS3 is derived from a single functional study (PMID:10468619) identified by automated literature search; the full text has not been independently verified. If PS3 is not upheld on human review, the combination would be 2 Moderate + 1 Supporting, which does not meet the Likely Pathogenic threshold and would default to Variant of Uncertain Significance.

ClinVar classification is Uncertain significance (2 clinical laboratories, criteria provided, single submitter). This variant has been observed once in somatic cancers (COSMIC COSV105891454).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	c.151G>T is a missense variant (p.Val51Phe); PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice sites) under the ClinGen SVI PVS1 framework (PMC6185798). This variant does not fall into any PVS1-eligible category.	pvs1_generic_framework
PS1	Not assessed	No prior evidence that a different nucleotide change at c.151 resulting in the same amino acid change (p.Val51Phe) has been classified as pathogenic.
PS2	Not assessed	No de novo observation reported for this variant; parental testing data are unavailable.
PS3	Met	A functional study (PMID:10468619) demonstrated that p.Val51Phe fails to inhibit CDK4 kinase activity and is unable to induce G1 arrest in a p16-null cell line, consistent with loss of tumor suppressor function.
PS4	Not assessed	No case-control association data or sufficient unrelated proband counts with this variant identified to meet PS4 thresholds.
PS5	Not met	ClinVar classifies this variant as Uncertain significance; no reputable source has reported it as pathogenic.	clinvar
PM1	Met	Val51 is located at the start of the second ankyrin repeat domain (residues ~50-71) of p16INK4a, a critical functional domain essential for CDK4/CDK6 binding. Multiple pathogenic missense variants cluster in the ankyrin repeat domains, and the variant is absent from population databases, consistent with a mutational hot spot without benign variation.	gnomad_v2 gnomad_v4
PM2	Met	Absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, confirming this variant is not a common population polymorphism (allele frequency 0.0 in all population databases queried).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No different pathogenic missense variant at codon 51 (Val51) was identified in ClinVar or published literature to satisfy PM5 same-residue comparator requirements.	pm5_candidates
PM6	Not assessed	No instances of assumed de novo occurrence (variant absent in both parents with unconfirmed relationships) identified.
PP1	Not assessed	No co-segregation data in affected family members identified for this variant.
PP2	Met	CDKN2A is a tumor suppressor gene in which missense variants are a well-established mechanism of disease, particularly in the ankyrin repeat domains. The gene has a low rate of benign missense variation in its critical functional domains.
PP3	Not met	Computational predictors provide mixed results: REVEL score 0.561 (borderline, below typical 0.75 damaging threshold), BayesDel score 0.137 (consistent with benign range), and SpliceAI max delta 0.02 (no predicted splice impact). Multiple lines of computational evidence do not converge on a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No specific patient phenotype or family history data available for this variant assessment.
PP5	Not met	ClinVar classifies this variant as Uncertain significance; no reputable source has classified it as pathogenic.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0; allele frequency 0.0 is well below the >1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0; allele frequency 0.0 does not meet the >0.3% BS1 threshold for a dominant disorder.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Variant is absent from gnomAD; no observation in healthy adult individuals has been reported.	gnomad_v2 gnomad_v4
BS3	Not met	The available functional study (PMID:10468619) demonstrates a damaging effect on protein function; no well-established functional studies show a benign effect.
BS4	Not assessed	No segregation data available to evaluate lack of segregation with disease in affected family members.
BP1	Not met	CDKN2A pathogenic variants include both missense (particularly in the ankyrin repeat domains) and truncating variants; missense variants are a well-established disease mechanism for this gene.
BP2	Not assessed	No observation of this variant in trans with a known CDKN2A pathogenic variant identified; such an observation would be expected to be lethal or embryonic for this tumor suppressor gene.
BP3	N/A	Variant is a missense substitution, not an in-frame indel; BP3 applies only to in-frame insertions/deletions.
BP4	Not met	Computational evidence is mixed: REVEL score 0.561 is above the benign range, BayesDel 0.137 leans benign, and SpliceAI shows no splice impact. Multiple lines do not consistently suggest no impact on gene product.	revel bayesdel spliceai
BP5	Not assessed	No data available regarding an alternate molecular basis for disease in a proband carrying this variant.
BP6	Not met	ClinVar classifies this variant as Uncertain significance; no reputable source has classified it as benign.	clinvar
BP7	N/A	c.151G>T is a missense variant (p.Val51Phe), not a synonymous variant; BP7 applies only to silent variants with no predicted splice impact.
PM3	N/A	CDKN2A-associated disease (familial melanoma, pancreatic cancer) is inherited in an autosomal dominant pattern; PM3 applies to recessive disorders.
PM4	N/A	Variant is a missense substitution, not a non-repeat indel or stop-loss variant; PM4 applies only to protein-length-altering variants.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.