Classification rationale

PM2 VUS

CDK4 c.736C>T missense · exon 7

PM2 supporting: gnomAD v4.1 AF 9.91304e-06 is below the generic threshold of 0.0001, with zero homozygotes.

PM2 → VUS

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.

Gene diagram · NM_000075.4 · variants mapped to exon structure

CDK4 NM_000075.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 23 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 1

Strength Supporting Moderate Strong Very strong

PM2 supporting Pathogenic

Met at supporting strength: gnomAD v4.1 AF 9.91304e-06 is below the generic PM2 threshold of 0.0001, with zero homozygotes.

gnomAD v2.1 reports AF 2.78567e-05 from 7/251286 alleles and zero homozygotes.gnomAD v4.1 reports AF 9.91304e-06 from 16/1614036 alleles and zero homozygotes.The supplied generic ClinGen SVI PM2 supporting calibration is AF <=0.0001 (PMID:25741868).

gnomad_v2 ↗gnomad_v4 ↗

Assessed · not applied · 8 not met · 15 not assessed

Pathogenic

PS1 Not met: the available report describes the exact c.736C>T change, not a different nucleotide substitution producing CDK4 p.Arg246Cys.

PS2 Not assessed: no documented proband-parent genotypes or confirmed de novo testing are available for CDK4 c.736C>T.

PS3 Not assessed: the only variant-specific study used computational predictions and molecular dynamics, not a validated functional assay with experimental controls.

PS4 Not assessed: no case-control counts or validated enrichment statistic is available for the exact CDK4 c.736C>T variant.

PM1 Not assessed: no approved CDK4 domain table or residue-specific hotspot evidence establishes that Arg246 lies in a PM1-qualifying critical region.

PM3 Not assessed: no affected-proband observation, second pathogenic allele, phase result, or validated recessive CDK4 inheritance context is available.

PM5 Not assessed: no independently classified pathogenic alternate missense change at CDK4 residue Arg246 was documented.

PM6 Not assessed: no documented presumed de novo occurrence or parental testing context is available for CDK4 c.736C>T.

PP1 Not assessed: zero informative family meioses or variant-positive and variant-negative relatives are documented for CDK4 c.736C>T.

PP2 Not assessed: the evidence lacks validated CDK4 missense-mechanism and benign-missense-constraint data required for PP2.

PP3 Not met: REVEL 0.386 is below the supporting PP3 threshold of 0.644, and BayesDel lacks an applicable generic calibration.

PP4 Not assessed: no patient phenotype, family history, or disease-specific clinical presentation is documented for this exact variant.

PP5 Not met: the exact-variant ClinVar record has zero expert-panel submissions and an aggregate Uncertain significance classification.

Benign

BA1 Not met: gnomAD v4.1 overall AF 9.91304e-06 is far below the generic BA1 threshold of 0.05.

BS1 Not met: the highest reported gnomAD v4.1 population AF is 3.33322e-05, below the generic BS1 threshold of 0.01.

BS2 Not met: gnomAD v4.1 reports zero homozygotes among 16 observed variant alleles, with no qualifying healthy-carrier observation provided.

BS3 Not assessed: no validated controlled assay demonstrates normal CDK4 p.Arg246Cys function; the available study is computational only.

BS4 Not assessed: no tested unaffected relatives lacking CDK4 c.736C>T or informative non-segregation observations are documented.

BP1 Not assessed: no validated CDK4 framework shows truncating variants predominate while missense variants are generally benign.

BP2 Not assessed: no second pathogenic variant, cis/trans phase determination, affected-proband genotype, or family segregation result is available.

BP4 Not met: REVEL 0.386 exceeds the supporting BP4 threshold of 0.29, while BayesDel has no applicable generic benign calibration.

BP5 Not assessed: no patient phenotype or alternative pathogenic molecular explanation is documented for this case.

BP6 Not met: no exact-variant ClinVar expert panel classified this variant as Benign or Likely benign.

N/A · 4 PVS1 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 9.91304e-06; MAF= 0.00099%, 16/1614036 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 3.33322e-05; MAF= 0.00333%, 2/60002 alleles, homozygotes = 0); grpmax FAF= 6.15e-06.

v2.1

This variant is present in gnomAD v2.1 (AF= 2.78567e-05; MAF= 0.00279%, 7/251286 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000163292; MAF= 0.01633%, 1/6124 alleles, homozygotes = 0); grpmax FAF= 9.58e-06.

🇨🇦 CA

Not available in gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00099% · 16 / 1,614,036
0 hom · FAF 0.00062%

Admixed American 2 / 60,002	0.0033%
Remaining individuals 1 / 62,484	0.0016%
European (non-Finnish) 13 / 1,180,010	0.0011%

+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

gnomAD v2.1

0.0028% · 7 / 251,286
0 hom · FAF 0.00096%

Remaining individuals 1 / 6,124	0.016%
African/African American 1 / 16,198	0.0062%
Admixed American 2 / 34,588	0.0058%
European (non-Finnish) 3 / 113,648	0.0026%

+ 4 not observed (Ashkenazi Jewish, East Asian, European (Finnish), South Asian)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 141602)

ClinVar ↗

In silico

SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. REVEL score = 0.386. BayesDel score = -0.141968.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDK4, an intracellular kinase, is altered by amplification or mutation in various cancer types including soft tissue sarcomas and gliomas.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57277471, n = 1 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 5 PMIDs not cited in assessment

21520333 ↗ LOVD v.2.0: the next generation in gene variant databases. CLINVAR

25394175 ↗ A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. CLINVAR

26252490 ↗ Analysing the Effect of Mutation on Protein Function and Discovering Potential Inhibitors of CDK4: Molecular Modelling and Dynamics Studies. CLINVAR

26389258 ↗ Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version. CLINVAR

26389333 ↗ Genetics of Skin Cancer (PDQ®): Health Professional Version. CLINVAR

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