Variant classification summary

NM_000075.3:c.803G>A

CDK4 · NP_000066.1:p.(Gly268Glu) · NM_000075.3

GRCh37: chr12:58142981 C>T · GRCh38: chr12:57749198 C>T

Gene: CDK4 Transcript: NM_000075.3

Final call

VUS

PM2 supporting

Variant details

Gene

CDK4

Transcript

NM_000075.3

Protein

NP_000066.1:p.(Gly268Glu)

gnomAD AF

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): the exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.

2

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.

Final determination: Generic ACMG/AMP 2015 fallback: with only PM2 (supporting) met and no other pathogenic or benign criteria met, none of the defined Pathogenic/Likely Pathogenic/Benign/Likely Benign combinations are satisfied, 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	Not applicable: this missense change does not trigger any null-variant mechanism such as nonsense-mediated decay.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic variant producing the identical amino-acid change p.Gly268Glu was identified.	pm5_candidates
PS2	Not assessed	Not assessed: no de novo occurrence or parental testing results were available.
PS3	Not assessed	Not assessed: no validated functional assay evidence for p.Gly268Glu was identified.
PS4	Not assessed	Not assessed: no case-control or affected-case series data for this exact variant were provided.	clinvar
PM1	Not met	Not met: codon 268 shows no hotspot signal, with no CancerHotspots, COSMIC, or OncoKB support at this position.	oncokb
PM2	Met	Met (supporting): the exact variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no evidence that the variant occurs in trans with a pathogenic allele for a recessive disorder.	PMID:25741868
PM4	N/A	Not applicable: missense substitution, so no change in protein length occurs.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at codon 268 previously established as pathogenic was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo occurrence without parental testing was reported.
PP1	Not assessed	Not assessed: no affected relatives or segregation data were documented.
PP2	Not assessed	Not assessed: no gene-level missense-constraint metric was available to evaluate CDK4's missense tolerance.
PP3	Not met	Not met: REVEL 0.469 lies between the benign-supporting (≤0.290) and pathogenic-supporting (≥0.644) cutoffs.	revel spliceai
PP4	Not assessed	Not assessed: no phenotype data establishing a well-defined disease match for this patient was provided.
PP5	Not met	Not met: ClinVar contains only two single-submitter uncertain-significance laboratory assertions, with no expert-panel submission.	clinvar
BA1	Not met	Not met: variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, far below the 5% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not assessed	Not assessed: no maximum credible allele frequency was available to define the benign frequency threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	Not assessed: no observations in unaffected adults or homozygotes were reported.	gnomad_v2 gnomad_v4 gnomad_canada
BS3	Not assessed	Not assessed: no functional assay evidence showing normal activity was identified.
BS4	Not assessed	Not assessed: no family genotyping data to evaluate segregation with disease.
BP1	Not assessed	Not assessed: no curated gene-mechanism data to evaluate whether missense variation is atypical for CDK4.
BP2	Not assessed	Not assessed: no evidence that the variant occurs in cis with a pathogenic variant.	PMID:25741868
BP3	N/A	Not applicable: missense substitution, so no in-frame indel in a repetitive region is involved.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.469 exceeds the ≤0.290 benign-supporting cutoff, and no splice impact is predicted.	revel spliceai
BP5	Not assessed	Not assessed: no evidence the variant causes a different disease while being evaluated for this condition.	clinvar
BP6	Not met	Not met: no expert-panel benign classification exists; available ClinVar submissions are uncertain significance.	clinvar
BP7	N/A	Not applicable: missense substitution, so the silent-variant premise does not apply.	generic_acmg_combination_rules

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.