CDK4 (cyclin-dependent kinase 4) is a serine/threonine kinase that drives cell cycle progression through the G1 to S phase transition. Together with its partner cyclin D, it phosphorylates and inactivates the retinoblastoma (RB) protein, releasing the E2F transcription program that promotes cell division, and its activity is held in check by the inhibitor p16(INK4a). Disruption of CDK4 and its related regulators is associated with tumorigenesis in a wide range of cancers, and amplification or overexpression of CDK4 is seen in sarcomas, glioblastoma, and breast cancer. CDK4/6 inhibitors have shown clinical benefit in certain solid tumors, including breast and non-small cell lung cancer.
This variant
CDK4 drives the G1-to-S cell-cycle transition, and germline gain-of-function changes (notably loss of p16 binding at residue Arg24) cause familial melanoma, while amplification drives many sporadic cancers. This VUS at codon 268 is not implicated in any of these mechanisms: it shows no hotspot or functional evidence, yet its absence from population databases prevents calling it benign. The classification therefore leaves p.Gly268Glu indeterminate for CDK4-mediated cancer risk.
Transcript
NM_000075.3
HGVS · transcript:coding
NM_000075.3:c.803G>A
GRCh38
chr12:57749198 C>T
GRCh37
chr12:58142981 C>T
BasisVUS: no CDK4 ClinGen VCEP was available, so generic ACMG/AMP 2015 rules applied; only PM2 (supporting) was met, below any classification threshold.▾
VUS: no CDK4 ClinGen VCEP was available, so generic ACMG/AMP 2015 rules applied; only PM2 (supporting) was met, below any classification threshold.
Classification rationale
PM2VUS
CDK4 c.803G>Amissense · exon 7
PM2 (Supporting): the exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0. Overall classification VUS: the single supporting PM2 criterion does not reach any Likely Pathogenic, Pathogenic, Likely Benign, or Benign combination threshold under generic ACMG/AMP 2015 rules.
PM2→VUS
Gene diagram
· NM_000075.3 · variants mapped to exon structure
CDK4NM_000075.3
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CDK4—click a row to locate it on the plot · use the link column to open its page
Variant ↕
Protein
Location
Classification
Link
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
✓
PM2supportingPathogenic
Met (supporting): the exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.
The exact variant is absent from gnomAD v2.1.The exact variant is absent from gnomAD v4.1.The exact variant is absent from gnomAD-Canada v1.0.
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.
Triaged references · 3 PMIDs not cited in assessment
25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.CLINVAR
26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.CLINVAR
26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.CLINVAR
