NM_001798.4:c.665C>T

CDK2 · NP_001789.2:p.(Pro222Leu) · NM_001798.4

GRCh37: chr12:56364904 C>T · GRCh38: chr12:55971120 C>T

Gene: CDK2 Transcript: NM_001798.4

Final call

VUS

PM2 supporting

Variant details

Gene

CDK2

Transcript

NM_001798.4

Protein

NP_001789.2:p.(Pro222Leu)

gnomAD AF

ClinVar

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001798.4:c.665C>T (p.Pro222Leu) in CDK2 is absent from population databases (gnomAD v2.1 and v4.1), meeting PM2 at supporting strength.

No other ACMG/AMP criterion was met. The variant lacks ClinVar classification, functional studies, de novo observations, segregation data, hotspot localization, same-residue pathogenic comparators, and conclusive in silico evidence.

With only one supporting criterion (PM2_supporting) and no other criteria met in either the pathogenic or benign direction, this variant is classified as a Variant of Uncertain Significance (VUS) per 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	N/A	This is a missense variant (c.665C>T, p.Pro222Leu) that does not fall into the PVS1 null-variant categories of nonsense, frameshift, or canonical ±1,2 splice consensus variants. Per ClinGen SVI PVS1 recommendations (PMC6185798), generic PVS1 is not applicable to missense variants.	pvs1_generic_framework
PS1	Not assessed	No known pathogenic nucleotide change at the same position (c.665) producing the same amino acid change (p.Pro222Leu) was identified in ClinVar or the literature.	clinvar pm5_candidates
PS2	Not assessed	No de novo observation of NM_001798.4:c.665C>T was identified in the literature or ClinVar. No parentage-confirmed de novo reports are available.	clinvar
PS3	Not assessed	No well-established in vitro or in vivo functional studies were identified for this specific variant (NM_001798.4:c.665C>T, p.Pro222Leu) in CDK2.
PS4	Not assessed	No case-control data or statistical enrichment analysis was identified for this variant in any disease cohort.
PS5	Not assessed	No alternative pathogenic missense change at residue Pro222 was identified. The PM5 candidate search returned zero same-residue comparators; ClinVar contains no entries for this variant.	pm5_candidates clinvar
PM1	Not met	This variant does not lie in a statistically significant mutational hotspot (CancerHotspots). Residue 222 resides within the CDK2 kinase domain, but no evidence was provided that this is a well-established critical functional domain lacking benign missense variation in the germline disease context.
PM2	Met	This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 population databases, consistent with a rare variant.	gnomad_v2 gnomad_v4
PM5	Not assessed	No same-residue pathogenic comparator variants (different missense change at Pro222) were identified in ClinVar. PM5 candidate harvesting yielded zero comparators; no published alternative missense at residue 222 was found.	pm5_candidates clinvar
PM6	Not assessed	No de novo observation of NM_001798.4:c.665C>T was identified. PM6 requires a de novo observation (with or without confirmed parentage), and none was found in ClinVar or the literature.	clinvar
PP1	Not assessed	No segregation data are available for this variant.
PP2	Not assessed	HCI prior scores are not available for CDK2. Without missense constraint metrics (e.g., Z-score, missense depletion), it cannot be determined whether CDK2 has a low rate of benign missense variation to support PP2.
PP3	Not met	In silico evidence is equivocal. REVEL score is 0.661 (below the 0.75 threshold typically used for computational pathogenicity support), BayesDel score is -0.044 (benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.02). These do not constitute multiple lines of computational evidence supporting a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype information is available. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology.
PP5	Not assessed	No reputable source (e.g., ClinGen-recognized expert panel, clinical diagnostic laboratory) has reported this variant as pathogenic. The variant is absent from ClinVar.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1 and v4.1 population databases. Allele frequency is 0%, far below the BA1 threshold of >5%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant is absent from population databases (gnomAD v2.1, v4.1). Allele frequency does not exceed the expected prevalence threshold for a rare disorder.	gnomad_v2 gnomad_v4
BS2	Not assessed	No observation of this variant in a healthy adult individual has been reported for a fully penetrant disorder. No genotype-phenotype data available.
BS3	Not assessed	No well-established in vitro or in vivo functional studies showing no deleterious effect were identified for NM_001798.4:c.665C>T in CDK2.
BS4	Not assessed	No nonsegregation data are available for this variant.
BP1	Not assessed	While loss of function is supported as a CDK2 germline disease mechanism (pvs1_gene_context: lof_mechanism_supported=true), CDK2 is not an established disease gene where primarily truncating variants are known to cause disease. Insufficient evidence to apply BP1.
BP2	Not assessed	No observation of this variant in trans with a known pathogenic variant in CDK2 was identified.
BP4	Not met	In silico evidence is equivocal and does not constitute multiple lines of computational evidence suggesting no impact. REVEL 0.661 is above the benign range; BayesDel -0.044 is mildly benign-leaning; SpliceAI max delta 0.02 shows no splicing effect. The aggregate evidence is insufficient for BP4.	revel bayesdel spliceai
BP5	Not assessed	No observation of this variant in a case where an alternate molecular basis for disease was identified.
BP6	Not assessed	No reputable source reports this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	This is a missense variant (c.665C>T, p.Pro222Leu), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splicing impact.
BP3	N/A	This variant is a single-nucleotide missense substitution, not an in-frame insertion or deletion in a repetitive region.
PM3	N/A	No second pathogenic variant in trans was identified. PM3 is for recessive disorders; no recessive CDK2 disorder is established, and no trans observation data exist.
PM4	N/A	This variant is a single-nucleotide missense substitution (c.665C>T), not a protein-length-altering in-frame deletion or insertion or stop-loss variant.

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