NM_001259.8:c.745C>T

CDK6 · NP_001250.1:p.(Leu249Phe) · NM_001259.8

GRCh37: chr7:92247475 G>A · GRCh38: chr7:92618161 G>A

Gene: CDK6 Transcript: NM_001259.8

Final call

VUS

PM2 supporting BP4 supporting benign

Variant details

Gene

CDK6

Transcript

NM_001259.8

Protein

NP_001250.1:p.(Leu249Phe)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001259.8:c.745C>T (p.Leu249Phe) is a missense variant in CDK6 exon 7. It is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting level.

Computational evidence unanimously predicts a benign effect: REVEL score 0.099, BayesDel score -0.356566, SpliceAI max delta 0.01. BP4 is met at supporting benign level.

The variant is absent from ClinVar and COSMIC. No functional studies or clinical case reports exist for this variant. OncoKB classifies p.Leu249Phe as 'Unknown Oncogenic Effect' with no variant-specific reviewed evidence.

Residue Leu249 is not a statistically significant cancer hotspot (cancerhotspots.org), and no literature characterizes this residue as a critical functional domain.

Under generic ACMG/AMP 2015 criteria, one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) are present. These offset each other, resulting in a classification of Variant of Uncertain Significance (VUS).

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	c.745C>T is a missense variant (p.Leu249Phe). Under ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is reserved for null variants (nonsense, frameshift, canonical ±1,2 splice consensus, initiation codon, single/multi-exon deletion). Missense variants do not qualify for PVS1.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	PS1 requires a different nucleotide change at the same codon resulting in the same amino acid (p.Leu249Phe) that has been established as pathogenic. No alternate nucleotide change producing p.Leu249Phe has been reported in ClinVar, the literature, or population databases.	clinvar gnomad_v2 gnomad_v4
PS2	Not assessed	No de novo data available. The variant is absent from ClinVar and no publications report de novo occurrence for NM_001259.8:c.745C>T.
PS3	Not met	No functional studies have been reported for p.Leu249Phe in CDK6. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No PMIDs mention this variant. CDK6 is an intracellular kinase amplified in some cancers, but no experimental data characterize this specific substitution.	oncokb
PS4	Not assessed	No patient or cohort data available. The variant is absent from ClinVar and no publications report cases harboring NM_001259.8:c.745C>T. Without proband counts or case-control data, PS4 cannot be evaluated.
PS5	N/A	PS5 (same codon, different missense change established as pathogenic) has been functionally subsumed into PM5 by ClinGen. No pathogenic missense variants at codon 249 were identified in ClinVar or the literature, so no comparator exists for this criterion.	pm5_candidates
PM1	Not met	Residue Leu249 is located within the CDK6 kinase domain, but cancerhotspots.org does not identify this residue as a statistically significant mutational hotspot. The variant is absent from COSMIC and ClinVar. No literature specifically characterizes residue Leu249 as a critical functional residue or established mutational hotspot in CDK6.	clinvar
PM2	Met	NM_001259.8:c.745C>T is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes). Under generic ACMG/AMP, absence from large population cohorts meets PM2 at supporting level.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 requires a different pathogenic missense change at the same amino acid residue (Leu249). The automated PM5 candidate search found zero same-residue ClinVar candidates at codon 249. No comparator variant exists to satisfy PM5.	pm5_candidates
PM6	Not assessed	No de novo data available. The variant is absent from ClinVar and no publications report de novo occurrence without confirmed maternity/paternity for NM_001259.8:c.745C>T.
PP1	Not assessed	No co-segregation data available. No family studies or pedigrees reporting NM_001259.8:c.745C>T were identified.
PP2	Not met	PP2 applies when a missense variant occurs in a gene with a low rate of benign missense variation and missense variants are a common mechanism of disease. CDK6 is not a well-established germline disease gene; the HCI prior was not found for CDK6. The gene is primarily associated with somatic alterations (amplifications) in cancer. The literature identified as supporting germline LoF mechanism (PVS1 gene context) consists of studies mentioning CDK6 as an interactor of CDKN2A/CDKN2B or as part of a broad cancer gene panel, not as a primary germline disease gene.	pvs1_gene_context
PP3	Not met	Multiple in silico tools unanimously predict a benign effect. REVEL score is 0.099 (well below the pathogenic threshold of >0.5). BayesDel score is -0.356566 (below typical pathogenic thresholds). SpliceAI predicts no splicing impact (max delta score 0.01). No computational tool supports a deleterious effect.	revel bayesdel spliceai
PP4	Not assessed	No patient phenotype or family history data available. PP4 requires that the variant is found in a patient with a phenotype and family history highly specific for the gene/disease. Without clinical data, this criterion cannot be assessed.
PP5	Not met	PP5 requires a reputable source (e.g., clinical diagnostic laboratory) to have classified this variant as pathogenic. NM_001259.8:c.745C>T is absent from ClinVar entirely and no diagnostic laboratory report has classified this variant.	clinvar
BA1	Not met	BA1 requires an allele frequency >1% in population databases. NM_001259.8:c.745C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with an allele count of zero across all cohorts.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	BS1 requires an allele frequency >0.3% in population databases. NM_001259.8:c.745C>T is absent from all gnomAD cohorts (v2.1, v4.1, Canada) with zero alleles observed.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	BS2 requires observation of the variant in a healthy adult individual, either in homozygous state or in trans with a known pathogenic variant. No such data are available for NM_001259.8:c.745C>T.
BS3	Not met	BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. No functional studies have been performed on p.Leu249Phe. OncoKB lists the variant as 'Unknown Oncogenic Effect' without any variant-specific functional evidence. In the absence of any functional data, BS3 cannot be met.	oncokb
BS4	Not assessed	BS4 requires lack of segregation in affected family members. No segregation or family data are available for this variant.
BP1	N/A	BP1 applies to a missense variant in a gene for which primarily truncating variants are known to cause disease. CDK6 is not an established germline disease gene where truncating variants are the primary pathogenic mechanism. The PVS1 gene context identifies literature mentioning germline context, but none of the cited papers establish CDK6 truncating variants as a primary cause of a defined Mendelian disorder.	pvs1_gene_context
BP2	Not assessed	BP2 requires observation of the variant in trans with a known pathogenic variant (for recessive disorders) or in cis with a pathogenic variant for a fully penetrant dominant disorder. No phase or genotype data are available for NM_001259.8:c.745C>T.
BP4	Met	Multiple lines of computational evidence unanimously predict a benign effect. REVEL score is 0.099 (strongly benign-leaning; pathogenic threshold typically >0.5). BayesDel score is -0.356566 (below benign/pathogenic cutoff). SpliceAI predicts no splicing impact (max delta score 0.01). No computational tool suggests a deleterious effect.	revel bayesdel spliceai
BP5	Not assessed	BP5 requires that the variant is found in a case with an alternate molecular basis for disease. No such data are available for NM_001259.8:c.745C>T.
BP6	Not met	BP6 requires a reputable source to have classified this variant as benign. NM_001259.8:c.745C>T is absent from ClinVar entirely; no diagnostic laboratory or reputable source has classified this variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. NM_001259.8:c.745C>T is a missense variant (p.Leu249Phe), not synonymous.

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