NM_000075.4:c.719G>C

CDK4 · NP_000066.1:p.(Arg240Pro) · NM_000075.4

GRCh37: chr12:58143065 C>G · GRCh38: chr12:57749282 C>G

Gene: CDK4 Transcript: NM_000075.4

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CDK4

Transcript

NM_000075.4

Protein

NP_000066.1:p.(Arg240Pro)

gnomAD AF

2.4780107520886533e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000075.4:c.719G>C (p.Arg240Pro) is a missense variant in CDK4 exon 7, currently classified as Uncertain significance by five clinical laboratories in ClinVar (Variation ID: 495534).

This variant is extremely rare in population databases, observed in 2 of 251,364 alleles (AF=0.0008%) in gnomAD v2.1 and 4 of 1,614,198 alleles (AF=0.00025%) in gnomAD v4.1, with no homozygotes, meeting PM2 at supporting strength.

Multiple in silico tools predict a benign effect: REVEL score 0.097, BayesDel score -0.331, and SpliceAI max delta 0.02, meeting BP4 at supporting benign strength.

No variant-specific functional data, de novo observations, case-control data, or segregation data were identified to support other pathogenic or benign criteria.

The variant is in the CDK4 protein kinase domain at residue Arg240, but no statistically significant hotspot or domain-level PM1 specification was found in the current evidence.

Overall, the evidence for pathogenicity (PM2_supporting) is balanced by evidence for a benign effect (BP4_supporting), yielding a classification of Uncertain significance under the generic ACMG/AMP 2015 framework.

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	NM_000075.4:c.719G>C is a missense variant (p.Arg240Pro) and does not fall into the generic PVS1 null-variant categories (nonsense, frameshift, or canonical splice site variants).	pvs1_generic_framework pvs1_variant_assessment
PS1	Not met	No alternative nucleotide change at the same codon producing the same amino acid change (p.Arg240Pro) has been reported as pathogenic.
PS2	Not met	No de novo occurrence data is available for this variant.
PS3	Not met	No variant-specific functional data is available. OncoKB reports Unknown Oncogenic Effect; no experimental studies of NM_000075.4:c.719G>C (p.Arg240Pro) were identified in the literature reviewed.	oncokb
PS4	Not met	No case-control or cohort data demonstrating enrichment of this variant in affected individuals versus controls is available. ClinVar submissions are all VUS with no phenotype enrichment data.	clinvar
PS5	Not met	The variant has not been reported as a definitive disease-causing mutation in a reputable source; ClinVar reports it as Uncertain significance by all submitters.	clinvar
PM1	Not met	Residue Arg240 is within the CDK4 protein kinase domain, but the residue is not identified as a statistically significant hotspot (cancerhotspots.org), and no VCEP/CSPEC domain specification or critical-domain literature citation is present in the case materials to support PM1 application.
PM2	Met	This variant is absent or extremely rare in large population databases. In gnomAD v2.1, it is observed in 2/251,364 alleles (AF=0.0008%), and in gnomAD v4.1 in 4/1,614,198 alleles (AF=0.00025%), with no homozygotes in either dataset. Both frequencies are well below the 0.1% threshold for PM2.	gnomad_v2 gnomad_v4
PM5	N/A	PM5 candidate harvesting was unable to confirm classic same-residue comparator variants; no same-position pathogenic missense comparators were identified.
PM6	Not met	No de novo observation is reported for this variant.
PP1	Not met	No segregation data with the disease phenotype is available for this variant.
PP2	Not met	No gene-level missense constraint metric (Z-score, missense depletion ratio) is available in the case materials to assess whether CDK4 has a low rate of benign missense variation.
PP3	Not met	Multiple in silico predictors support a benign effect: REVEL score is 0.097 (well below pathogenicity threshold of ~0.5), BayesDel score is -0.331 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta = 0.02). These data support BP4 rather than PP3.	revel bayesdel spliceai
PP4	Not met	No case-specific phenotype or family history data is available to assess whether the patient's presentation is highly specific for CDK4-related disease.
PP5	Not met	ClinVar reports this variant as Uncertain significance with review status 'criteria provided, single submitter' (1-star). Under the global PP5 rule, supporting strength requires a 3-star expert panel review classification of pathogenic/likely pathogenic, which is not met.	clinvar
BA1	Not met	The variant allele frequency in gnomAD (v2.1: 0.0008%, v4.1: 0.00025%) is far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4
BS1	Not met	The variant allele frequency in gnomAD (v2.1: 0.0008%, v4.1: 0.00025%) is below the BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4
BS2	Not met	No data is available demonstrating observation of this variant in healthy adults at sufficient frequency to meet BS2.
BS3	Not met	No well-established functional studies demonstrate a benign effect of this variant. No experimental data for p.Arg240Pro was identified in the reviewed literature.	oncokb
BS4	Not met	No segregation data is available to evaluate lack of cosegregation with disease.
BP1	N/A	CDK4 germline disease is associated with missense variants (e.g., R24C/H in familial melanoma), not predominantly truncating variants. BP1 applies when primarily truncating variants cause disease.
BP2	Not met	No data is available demonstrating this variant observed in trans with a known pathogenic variant.
BP4	Met	Multiple lines of computational evidence support a benign effect: REVEL score is 0.097 (benign), BayesDel score is -0.331 (benign), and SpliceAI predicts no splicing impact (max delta = 0.02). No in silico predictor suggests pathogenicity.	revel bayesdel spliceai
BP5	Not met	No data is available demonstrating this variant in a case with an established alternative molecular basis for disease.
BP6	Not met	ClinVar reports this variant as Uncertain significance, not benign/likely benign. The review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold required for BP6 application.	clinvar
BP7	N/A	This is a missense variant (c.719G>C, p.Arg240Pro) located in exon 7. BP7 applies only to synonymous variants or intronic variants outside splice consensus.

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.