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CDK6c.745C>TUncertain significance
Print report
Variant interpretation report

CDK6 c.745C>T, p.(Leu249Phe)

NM_001259.8:c.745C>T NP_001250.1:p.(Leu249Phe) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About CDK6

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.010 maximum delta

Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 10 not met · 9 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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).

Met · 2

PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles).
  • Absent from gnomAD v4.1 (0 alleles).
  • Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.099.
  • BayesDel: -0.356566.
  • SpliceAI: max delta 0.01.
Sources
revelbayesdelspliceai ↗

Not met · 10 · evaluated, threshold not reached

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. No alternate nucleotide change producing p.Leu249Phe has been reported in ClinVar, the literature, or population databases. Details ▾Hide ▴
Evidence considered
  • No alternate nucleotide change at codon 249 producing Leu249Phe identified in any database.
Still missing
  • No alternate nucleotide change at codon 249 has been reported.
Sources
clinvar ↗gnomad_v2 ↗gnomad_v4 ↗
PS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • not reviewed
  • no variant-specific functional evidence.
Still missing
  • No experimental functional characterization of p.Leu249Phe exists in the literature.
Sources
oncokb ↗
PM1 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. Details ▾Hide ▴
Evidence considered
  • Cancerhotspots.org: residue L249 not a significant hotspot. COSMIC: absent. No literature supporting a critical functional domain at this specific residue.
Still missing
  • No evidence that Leu249 is a mutational hotspot or critical functional residue.
Sources
clinvar ↗
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. 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. Details ▾Hide ▴
Evidence considered
  • HCI prior not found for CDK6.
  • No established germline disease for CDK6 where missense is a common mechanism.
Still missing
  • CDK6 is not a recognized germline disease gene meeting PP2 criteria.
Sources
pvs1_gene_context
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.099 (benign-leaning).
  • BayesDel: -0.356566 (benign-leaning).
  • SpliceAI: max delta 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP5 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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no reputable source has reported it as pathogenic.
Sources
clinvar ↗
BA1 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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from all gnomAD cohorts (allele frequency = 0.0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from all gnomAD cohorts (allele frequency = 0.0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS3 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. Details ▾Hide ▴
Evidence considered
  • OncoKB: Unknown Oncogenic Effect
  • no variant-specific functional evidence available.
Still missing
  • No functional studies characterizing p.Leu249Phe exist.
Sources
oncokb ↗
BP6 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. Details ▾Hide ▴
Evidence considered
  • Variant is absent from ClinVar
  • no reputable source has classified it as benign.
Sources
clinvar ↗

Not assessed · 9 · no assessment recorded

PS2 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. Details ▾Hide ▴
Still missing
  • No proband or parental genotype data available to assess de novo status.
PS4 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. Details ▾Hide ▴
Still missing
  • No clinical cases or cohort data available for this variant.
PM6 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. Details ▾Hide ▴
Still missing
  • No de novo case reports available.
PP1 No co-segregation data available. No family studies or pedigrees reporting NM_001259.8:c.745C>T were identified. Details ▾Hide ▴
Still missing
  • No segregation data from affected families.
PP4 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. Details ▾Hide ▴
Still missing
  • No proband phenotype or clinical history data available.
BS2 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. Details ▾Hide ▴
Still missing
  • No data on healthy adult carriers or phase information.
BS4 BS4 requires lack of segregation in affected family members. No segregation or family data are available for this variant. Details ▾Hide ▴
Still missing
  • No family segregation data available.
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. No phase or genotype data are available for NM_001259.8:c.745C>T. Details ▾Hide ▴
Still missing
  • No phase or co-occurrence data available.
BP5 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. Details ▾Hide ▴
Still missing
  • No case data with alternate molecular diagnosis.
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/Ac.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. Details ▾Hide ▴
Evidence considered
  • Variant class: missense substitution
  • does not fall into any PVS1 null-variant bucket.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/APM5 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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search: 0 same-residue candidates
  • 0 total comparators.
Sources
pm5_candidates
BP1 N/ABP1 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. Details ▾Hide ▴
Evidence considered
  • CDK6 is not an established germline disease gene with a truncating mechanism for which BP1 would apply.
Sources
pvs1_gene_context
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001259.8:c.745C>T is a missense variant (p.Leu249Phe), not synonymous. Details ▾Hide ▴
Evidence considered
  • Variant is missense (p.Leu249Phe)
  • not synonymous.
PS5 N/APS5 (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. Details ▾Hide ▴
Evidence considered
  • PM5 candidate search found 0 same-residue comparator variants at codon 249 in ClinVar.
Sources
pm5_candidates

Identifiers

Gene
CDK6
Transcript
NM_001259.8
Coding (HGVS c.)
NM_001259.8:c.745C>T
Protein (HGVS p.)
NP_001250.1:p.(Leu249Phe)
GRCh38
chr7:92618161 G>A
GRCh37
chr7:92247475 G>A

Gene diagram

Every interpreted variant in CDK6, mapped onto the exon structure of NM_001259.8. Select a row to find it on the plot.

CDK6NM_001259.8
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +46 bp
0.000
SpliceAI acceptor gainat -8 bp
0.010
SpliceAI donor lossat +343 bp
0.000
SpliceAI donor gainat -7 bp
0.000
Pangolin splice lossmagnitude shown
-0.000
Pangolin splice gain
0.000

Other predictors

REVEL
0.099
BayesDel
-0.357

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.099.
  • BayesDel: -0.356566.
  • SpliceAI: max delta 0.01.
Sources
revelbayesdelspliceai ↗
PP3 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. Details ▾Hide ▴
Evidence considered
  • REVEL: 0.099 (benign-leaning).
  • BayesDel: -0.356566 (benign-leaning).
  • SpliceAI: max delta 0.01 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. NM_001259.8:c.745C>T is a missense variant (p.Leu249Phe), not synonymous. Details ▾Hide ▴
Evidence considered
  • Variant is missense (p.Leu249Phe)
  • not synonymous.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.099. BayesDel score = -0.356566.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.010 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

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

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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.