NM_000075.4:c.823A>T

CDK4 · NP_000066.1:p.(Met275Leu) · NM_000075.4

GRCh37: chr12:58142397 T>A · GRCh38: chr12:57748614 T>A

Gene: CDK4 Transcript: NM_000075.4

Final call

VUS

PM2 supporting PP2 supporting BP4 supporting benign

Variant details

Gene

CDK4

Transcript

NM_000075.4

Protein

NP_000066.1:p.(Met275Leu)

gnomAD AF

1.8608182389960514e-06 (v4.1)

ClinVar

Uncertain significance

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000075.4:c.823A>T (p.Met275Leu) is a missense variant in CDK4, a gene in which missense variants are a known mechanism of autosomal dominant hereditary melanoma.

This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-6 (1/251,446 alleles) and gnomAD v4.1 AF=1.86e-6 (3/1,612,194 alleles; grpmax FAF=6.8e-7), satisfying PM2 at supporting level.

The variant meets PP2 at supporting level: CDK4 has a low rate of benign missense variation and missense variants are a well-established disease mechanism (e.g., R24C/H in hereditary melanoma).

Multiple lines of in silico evidence support a benign interpretation: REVEL score 0.197 (<0.5), BayesDel score -0.0628 (negative), and SpliceAI max delta 0.00 (no splicing impact), satisfying BP4 at supporting benign level.

This variant has been reported in ClinVar as Uncertain Significance by three clinical laboratories (Variation ID 141405). No functional studies, segregation data, case-control comparisons, or de novo observations are available for this variant.

Two supporting pathogenic criteria (PM2, PP2) and one supporting benign criterion (BP4) net to one supporting pathogenic criterion, resulting in a final classification of Variant of Uncertain Significance (VUS) 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.823A>T is a missense variant (p.Met275Leu) and does not fall into any null-variant bucket (nonsense, frameshift, canonical ±1/2 splice consensus) required for PVS1 per the ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not met	No alternative nucleotide change at codon 275 yielding the same amino acid substitution (p.Met275Leu) has been reported as pathogenic in ClinVar, COSMIC, or the literature. No same-residue comparator variants were identified in the PM5 candidate search.	clinvar
PS2	Not met	No de novo occurrence of NM_000075.4:c.823A>T with confirmed maternity and paternity has been reported in the literature or public databases.
PS3	Not met	No well-established functional studies have been performed for the p.Met275Leu variant. No kinase activity, binding, or cellular proliferation assays specific to this variant were identified.	oncokb
PS4	Not met	No case-control study comparing the prevalence of NM_000075.4:c.823A>T in affected individuals versus controls has been published. The variant is observed at extremely low frequency in gnomAD (1/251,446 in v2.1; 3/1,612,194 in v4.1) but this alone is insufficient to satisfy PS4 without a statistically significant odds ratio.	gnomad_v2 gnomad_v4
PS5	Not met	No reputable source has reported NM_000075.4:c.823A>T as pathogenic. ClinVar classifies this variant as Uncertain Significance (3 clinical laboratories, criteria provided single submitter).	clinvar
PM1	Not met	Codon 275 resides in the C-terminal extension beyond the core kinase domain (residues ~6-295). Cancer Hotspots does not identify residue 275 as a statistically significant hotspot. Known CDK4 pathogenic missense variants cluster at codon 24 (R24C/H) in the N-terminal domain.
PM2	Met	NM_000075.4:c.823A>T is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-6 (1/251,446 alleles), gnomAD v4.1 AF=1.86e-6 (3/1,612,194 alleles; grpmax FAF=6.8e-7), and absent from gnomAD-Canada. All frequencies are well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM5	Not met	No pathogenic missense variant at codon 275 via a different amino acid substitution has been identified. PM5 candidate harvesting found zero comparator variants at this residue.
PM6	Not met	No assumed de novo occurrence of NM_000075.4:c.823A>T (without confirmation of paternity and maternity) has been reported.
PP1	Not met	No co-segregation data for NM_000075.4:c.823A>T with disease in affected families has been reported.
PP2	Met	CDK4 is a gene in which missense variants are a well-established mechanism of disease (e.g., R24C/H in hereditary melanoma) and which has a low rate of benign missense variation in the general population. PP2 is met at supporting level.	gnomad_v4
PP3	Not met	Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.197 (below 0.5 threshold), BayesDel score is -0.0628 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta=0.00).	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available for adjudication. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology.
PP5	Not met	No reputable source has reported NM_000075.4:c.823A>T as pathogenic. ClinVar classifies it as Uncertain Significance (Variation ID 141405). None of the associated ClinVar PMIDs (25394175, 26389258, 26389333, 28492532) mention this specific variant.	clinvar
BA1	Not met	The maximum allele frequency of NM_000075.4:c.823A>T in gnomAD is 8.79e-6 (v2.1 NFE) and 2.55e-6 (v4.1 NFE), both far below the BA1 threshold of 1% (0.01).	gnomad_v2 gnomad_v4
BS1	Not met	The maximum allele frequency of NM_000075.4:c.823A>T (8.79e-6 in gnomAD v2.1; 2.55e-6 in gnomAD v4.1) is well below the BS1 threshold of 0.3% (0.003) for non-VCEP adjudication.	gnomad_v2 gnomad_v4
BS2	Not met	Although NM_000075.4:c.823A>T is observed in gnomAD (3 heterozygous carriers in v4.1), CDK4-associated hereditary melanoma has incomplete penetrance and adult onset. BS2 requires observation in a healthy adult for a disorder with full penetrance expected at an early age; melanoma predisposition does not meet this threshold.	gnomad_v4
BS3	Not met	No well-established functional studies demonstrating no deleterious effect of the p.Met275Leu variant have been published.
BS4	Not met	No data demonstrating lack of co-segregation of NM_000075.4:c.823A>T with disease in affected families are available.
BP1	N/A	BP1 applies to missense variants in genes where primarily truncating variants cause disease. CDK4 hereditary melanoma is primarily caused by missense variants (gain-of-function, e.g., R24C/H), not truncating variants. BP1 is therefore not applicable.
BP2	Not met	No evidence of NM_000075.4:c.823A>T observed in trans with a pathogenic variant for CDK4. CDK4-associated disease is autosomal dominant; no recessive CDK4 phenotype is known.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions. NM_000075.4:c.823A>T is a single nucleotide substitution, not an in-frame indel.
BP4	Met	Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.197 (below 0.5 benign threshold), BayesDel score is -0.0628 (negative, consistent with benign), and SpliceAI max delta score is 0.00 (no predicted splicing alteration).	revel bayesdel spliceai
BP5	Not met	No evidence that NM_000075.4:c.823A>T was found in a case with an alternate molecular basis for disease. No such clinical data are available.
BP6	Not met	No reputable source has reported NM_000075.4:c.823A>T as benign. ClinVar classifies it as Uncertain Significance (Variation ID 141405), not benign or likely benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants not predicted to affect splicing. NM_000075.4:c.823A>T is a missense variant (p.Met275Leu), not synonymous.
PM3	N/A	PM3 applies to recessive disorders (variant detected in trans with a pathogenic variant). CDK4-associated disease is autosomal dominant; no recessive CDK4 phenotype is known.
PM4	N/A	PM4 applies to protein length changes due to in-frame deletions/insertions, stop-loss variants, or variants disrupting the initiation codon. NM_000075.4:c.823A>T is a single nucleotide missense substitution with no protein length alteration.

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