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.1 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.2 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.3 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).4
CDK6
Final classification
VUS
CDK6 c.745C>T · p.Leu249Phe
CDK6
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.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
CDK6 c.745C>T
PM2 + BP4
→
VUS
2
revelbayesdelspliceai ↗
4
generic_acmg_combination_rules
Gene diagram
· NM_001259.8 · variants mapped to exon structure
CDK6
NM_001259.8
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 19 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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.
Absent from gnomAD v2.1 (0 alleles).Absent from gnomAD v4.1 (0 alleles).Absent from gnomAD-Canada v1.0 (0 alleles).
✓
BP4
supporting
Benign
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: 0.099.BayesDel: -0.356566.SpliceAI: max delta 0.01.
Assessed · not applied
Pathogenic
PS1
PS1 requires a different nucleotide change at the same codon resulting in the same amino acid (p.Leu249Phe) that has been established as pathogenic.
PS2
No de novo data available.
PS3
No functional studies have been reported for p.Leu249Phe in CDK6.
PS4
No patient or cohort data available.
PM1
Residue Leu249 is located within the CDK6 kinase domain, but cancerhotspots.org does not identify this residue as a statistically significant mutational hotspot.
PM6
No de novo data available.
PP1
No co-segregation data available.
PP2
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.
PP3
Multiple in silico tools unanimously predict a benign effect.
PP4
No patient phenotype or family history data available.
PP5
PP5 requires a reputable source (e.g., clinical diagnostic laboratory) to have classified this variant as pathogenic.
Benign
BA1
BA1 requires an allele frequency >1% in population databases.
BS1
BS1 requires an allele frequency >0.3% in population databases.
BS2
BS2 requires observation of the variant in a healthy adult individual, either in homozygous state or in trans with a known pathogenic variant.
BS3
BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect.
BS4
BS4 requires lack of segregation in affected family members.
BP2
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.
BP5
BP5 requires that the variant is found in a case with an alternate molecular basis for disease.
BP6
BP6 requires a reputable source to have classified this variant as benign.
N/A · 4
PVS1 · PM5 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.099. BayesDel score = -0.356566.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDK6, an intracellular kinase, is amplified in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links