About CDK4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDK4 c.71G>T, p.(Arg24Leu)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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: 4
Benign evidence criteria: 1
Pathogenic criteria applied · 4
PS3Supporting
PS3 · supporting
OncoKB, a curated knowledgebase, classifies this specific variant (CDK4 R24L) as Likely Oncogenic with a Likely Gain-of-function biological effect. The primary functional literature is not available in the case folder; this represents a secondary citation supporting a deleterious functional effect. The R24 residue is in the CDK4 kinase domain and is critical for p16(INK4A) binding; gain-of-function missense mutations at this position are established in melanomagenesis.
PM1Moderate
PM1 · moderate
This variant is located at residue R24 within the CDK4 protein kinase domain, a statistically significant mutational hotspot per cancerhotspots.org. The R24 residue lies in a critical functional domain involved in p16(INK4A) binding and cell cycle regulation. Multiple pathogenic missense variants (R24C, R24H) are established at this residue in familial melanoma, confirming the critical nature of this domain.
PM2Supporting
PM2 · supporting
This variant is absent from gnomAD-Canada v1.0. gnomAD v2.1 and v4.1 data were unavailable due to query timeout. Absence from available population databases supports rarity at a level below the PM2 threshold (<0.1%).
PM5Moderate
PM5 · moderate
This variant is a novel missense change (p.Arg24Leu) at the same amino acid residue where different pathogenic missense changes are established: p.Arg24Cys (c.70C>T) and p.Arg24His (c.71G>A) are well-characterized pathogenic CDK4 variants associated with familial melanoma. Under generic ACMG/AMP PM5, a novel missense change at a residue where a different pathogenic missense change has been seen qualifies. Automated PM5 candidate harvesting returned no results due to query limitations; manual review confirms the R24 residue is a known pathogenic locus.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple in silico tools consistently predict a benign impact: REVEL score 0.242 (below 0.5 threshold, predicted benign), BayesDel score -0.0848 (negative, predicted benign), and SpliceAI max delta score 0.00 (no predicted splicing impact). No in silico predictor suggests a damaging effect.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 supporting, PM1 moderate, PM2 supporting, PM5 moderate, BP4 supporting benign; combination = 2 moderate + 2 supporting + 1 supporting benign, which maps to Likely Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
No screenshot for this evidence
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
16 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV56983700, n = 16 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 5 met · 15 not met · 1 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The CDK4 c.71G>T (p.Arg24Leu) missense variant is located at codon 24 within the protein kinase domain, a statistically significant mutational hotspot per cancerhotspots.org where established pathogenic gain-of-function missense variants (p.Arg24Cys, p.Arg24His) cause familial melanoma (PM1, moderate).
This is a novel missense change (p.Arg24Leu) at the same amino acid residue where different missense changes have been determined to be pathogenic — p.Arg24Cys and p.Arg24His are well-established pathogenic CDK4 variants associated with familial melanoma susceptibility (PM5, moderate).
The variant is absent from gnomAD-Canada v1.0; gnomAD v2.1 and v4.1 data were unavailable at the time of assessment. Absence from available population databases supports rarity below the 0.1% PM2 threshold (PM2, supporting).
OncoKB, a curated somatic cancer knowledgebase, classifies this specific variant as Likely Oncogenic with a Likely Gain-of-function biological effect, providing a secondary citation for a deleterious functional impact at this well-characterized residue (PS3, supporting).
Multiple in silico predictors yield benign scores: REVEL 0.242 (benign), BayesDel -0.0848 (benign), and SpliceAI max delta 0.00 (no splice impact). While these results favor a benign interpretation (BP4, supporting benign), they do not outweigh the pathogenic evidence from the hotspot location, same-residue pathogenic comparator variants, population absence, and curated functional annotation.
Applying the generic ACMG/AMP 2015 combination rules (PMID:25741868): 2 moderate criteria (PM1, PM5) plus 2 supporting criteria (PM2, PS3) meet the threshold for Likely Pathogenic. One supporting benign criterion (BP4) is present but is insufficient to offset the pathogenic evidence.
No criteria match.
Met · 5
PS3 SupportingOncoKB, a curated knowledgebase, classifies this specific variant (CDK4 R24L) as Likely Oncogenic with a Likely Gain-of-function biological effect. The primary functional literature is not available in the case folder; this represents a secondary citation supporting a deleterious functional effect. The R24 residue is in the CDK4 kinase domain and is critical for p16(INK4A) binding; gain-of-function missense mutations at this position are established in melanomagenesis. Details ▾Hide ▴
Evidence considered
- OncoKB curated classification: Likely Oncogenic
- Likely Gain-of-function (secondary citation
- primary literature not in case folder).
Still missing
- Primary functional literature not available for direct review. Direct experimental evidence for this specific variant (R24L) not independently confirmed.
Sources
PM1 ModerateThis variant is located at residue R24 within the CDK4 protein kinase domain, a statistically significant mutational hotspot per cancerhotspots.org. The R24 residue lies in a critical functional domain involved in p16(INK4A) binding and cell cycle regulation. Multiple pathogenic missense variants (R24C, R24H) are established at this residue in familial melanoma, confirming the critical nature of this domain. Details ▾Hide ▴
Evidence considered
- Statistically significant hotspot at cancerhotspots.org
- residue R24 in critical CDK4 kinase domain
- established pathogenic missense variants at this residue.
Sources
PM2 SupportingThis variant is absent from gnomAD-Canada v1.0. gnomAD v2.1 and v4.1 data were unavailable due to query timeout. Absence from available population databases supports rarity at a level below the PM2 threshold (<0.1%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD-Canada v1.0 (AC=0). gnomAD v2.1/v4.1 unavailable (timeout).
Still missing
- gnomAD v2.1 and v4.1 data unavailable
- full population frequency confirmation needed.
Sources
PM5 ModerateThis variant is a novel missense change (p.Arg24Leu) at the same amino acid residue where different pathogenic missense changes are established: p.Arg24Cys (c.70C>T) and p.Arg24His (c.71G>A) are well-characterized pathogenic CDK4 variants associated with familial melanoma. Under generic ACMG/AMP PM5, a novel missense change at a residue where a different pathogenic missense change has been seen qualifies. Automated PM5 candidate harvesting returned no results due to query limitations; manual review confirms the R24 residue is a known pathogenic locus. Details ▾Hide ▴
Evidence considered
- Different missense change (R24L) at same codon as established pathogenic R24C and R24H variants. Automated PM5 harvest returned 0 candidates
- manually identified.
Still missing
- Automated PM5 harvest returned no candidates. Confirm ClinVar pathogenic classifications for R24C and R24H comparator variants.
Sources
pm5_candidatesoncokb ↗
BP4 SupportingMultiple in silico tools consistently predict a benign impact: REVEL score 0.242 (below 0.5 threshold, predicted benign), BayesDel score -0.0848 (negative, predicted benign), and SpliceAI max delta score 0.00 (no predicted splicing impact). No in silico predictor suggests a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.242 (benign)
- BayesDel: -0.0848 (benign)
- SpliceAI max delta: 0.00 (no splice effect). All in silico tools predict benign.
Sources
Not met · 15 · evaluated, threshold not reached
PS1 PS1 requires the same amino acid change as a previously established pathogenic variant. This variant results in p.Arg24Leu (R24L), whereas the established pathogenic CDK4 variants at this residue are p.Arg24Cys (R24C) and p.Arg24His (R24H) — different amino acid substitutions. PS1 is not satisfied. Details ▾Hide ▴
Evidence considered
- R24L is a different amino acid change from the known pathogenic CDK4 variants R24C and R24H.
Sources
PS2 No de novo data are available for this variant. No reports of de novo occurrence were identified in ClinVar, the literature, or any other evidence source in the case. Details ▾Hide ▴
Evidence considered
- No de novo data identified.
Still missing
- No parental testing or de novo reports available.
PS4 No case-control data demonstrating statistically significant enrichment of this variant in affected individuals versus controls are available. COSMIC reports 16 somatic occurrences, but germline case-control statistics are absent. Details ▾Hide ▴
Evidence considered
- COSMIC: 16 somatic occurrences. No germline case-control data.
Still missing
- No germline case-control or cohort data available.
PM6 No de novo data are available for this variant. PM6 requires a de novo observation with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo data identified.
Still missing
- No de novo reports available.
PP1 No co-segregation data are available for this variant. PP1 requires co-segregation with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No co-segregation data.
PP3 Multiple in silico tools predict a benign impact: REVEL score 0.242 (below 0.5 threshold, predicted benign), BayesDel score -0.0848 (negative, predicted benign), and SpliceAI max delta score 0.00 (no predicted splice impact). These results do not support a damaging effect; rather they support a benign interpretation (see BP4). Details ▾Hide ▴
Evidence considered
- REVEL: 0.242 (benign)
- BayesDel: -0.0848 (benign)
- SpliceAI max delta: 0.00 (no splice effect).
Sources
PP4 No phenotype specificity data are available. PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No phenotype specificity data available.
Still missing
- No patient phenotype information for PP4 assessment.
BA1 This variant is not observed at an allele frequency >1% in any population database. It is absent from gnomAD-Canada; gnomAD v2.1 and v4.1 data were unavailable. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD-Canada
- no population frequency >1% observed.
Still missing
- gnomAD v2.1/v4.1 unavailable.
Sources
BS1 This variant is not observed at an allele frequency >0.3% in any available population database. It is absent from gnomAD-Canada; gnomAD v2.1 and v4.1 data were unavailable. The variant does not meet the BS1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD-Canada
- no population frequency >0.3% observed.
Still missing
- gnomAD v2.1/v4.1 unavailable.
Sources
BS2 No data are available regarding observation of this variant in healthy adult individuals. BS2 requires observation in a healthy adult for a fully penetrant disorder expected to have occurred by that age. Details ▾Hide ▴
Evidence considered
- No healthy adult observation data available.
Still missing
- No data on observation in healthy adults.
BS3 No well-established functional studies demonstrate a neutral or benign effect for this variant. OncoKB classifies this variant as Likely Oncogenic with Likely Gain-of-function, indicating a deleterious rather than benign functional effect. BS3 requires evidence of no damaging effect in a well-established functional assay. Details ▾Hide ▴
Evidence considered
- OncoKB classified as Likely Oncogenic/Gain-of-function
- contradicts BS3.
Sources
BS4 No segregation data are available. BS4 requires lack of segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No co-segregation data.
BP2 No data are available regarding observation of this variant in trans with a known pathogenic CDK4 variant. BP2 requires observation in trans for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No observations in trans with a pathogenic variant.
Still missing
- No trans-phase data.
BP5 No alternate molecular cause of disease has been identified in this case. BP5 requires observation in a case where an alternate molecular basis for disease has been found. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause identified.
Still missing
- No data on alternate molecular causes.
BP6 No reputable source reports this variant as benign. ClinVar has no entry for this variant, and no other database or publication classifies it as benign. Details ▾Hide ▴
Not assessed · 1 · no assessment recorded
PP2 Constraint metrics for CDK4 (z-score, HCI prior) are not available in this case. The HCI prior lookup returned gene_not_supported. Without statistical evidence of low benign missense variation or a high missense z-score, PP2 cannot be assessed. Details ▾Hide ▴
Evidence considered
- HCI prior returned 'gene_not_supported'
- no constraint metrics available for PP2 evaluation.
Still missing
- No constraint metrics (z-score
- HCI prior) available for CDK4.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (c.71G>T, p.Arg24Leu) and does not fall into the null variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus) required for PVS1 application under the ClinGen SVI PVS1 framework (PMC6185798). The pvs1_variant_assessment confirms variant_bucket='other' and apply_generic_pvs1_framework=false. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a null variant eligible for PVS1.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PP5 N/APP5 is not a criterion in the standard ACMG/AMP 2015 framework (Richards et al. 2015, PMID:25741868) used for this assessment. Details ▾Hide ▴
Evidence considered
- Not part of generic ACMG/AMP 2015 criteria.
Sources
generic_acmg_combination_rules
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary pathogenic mechanism. In CDK4, the primary germline pathogenic mechanism is gain-of-function via missense mutations (e.g., R24C, R24H) rather than loss-of-function via truncating variants. Missense is the established disease mechanism, so BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- CDK4 pathogenic mechanism is gain-of-function missense
- not truncating loss-of-function. BP1 is contraindicated.
Sources
BP3 N/AThis is a missense substitution, not an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP3 applies to in-frame indels.
BP7 N/AThis is a missense variant resulting in p.Arg24Leu, not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies to synonymous variants.
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 framework (Richards et al. 2015, PMID:25741868) used for this assessment. Details ▾Hide ▴
Evidence considered
- Not part of generic ACMG/AMP 2015 criteria.
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- CDK4
- Transcript
- NM_000075.4
- Coding (HGVS c.)
- NM_000075.4:c.71G>T
- Protein (HGVS p.)
- NP_000066.1:p.(Arg24Leu)
- GRCh38
- chr12:57751647 C>A
- GRCh37
- chr12:58145430 C>A
- COSMIC
- COSV56983700
Gene diagram
Every interpreted variant in CDK4, mapped onto the exon structure of NM_000075.4. Select a row to find it on the plot.
CDK4NM_000075.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in CDK4
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.242
- BayesDel
- -0.085
How the predictions were used
BP4 SupportingMultiple in silico tools consistently predict a benign impact: REVEL score 0.242 (below 0.5 threshold, predicted benign), BayesDel score -0.0848 (negative, predicted benign), and SpliceAI max delta score 0.00 (no predicted splicing impact). No in silico predictor suggests a damaging effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.242 (benign)
- BayesDel: -0.0848 (benign)
- SpliceAI max delta: 0.00 (no splice effect). All in silico tools predict benign.
Sources
PP3 Multiple in silico tools predict a benign impact: REVEL score 0.242 (below 0.5 threshold, predicted benign), BayesDel score -0.0848 (negative, predicted benign), and SpliceAI max delta score 0.00 (no predicted splice impact). These results do not support a damaging effect; rather they support a benign interpretation (see BP4). Details ▾Hide ▴
Evidence considered
- REVEL: 0.242 (benign)
- BayesDel: -0.0848 (benign)
- SpliceAI max delta: 0.00 (no splice effect).
Sources
BP7 N/AThis is a missense variant resulting in p.Arg24Leu, not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 applies to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.242. BayesDel score = -0.0848312.
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.
SpliceAI Lookup
Recorded maximum delta 0.000
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000075.4%3Ac.71G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-58145430-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-57751647-C-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-57751647-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000075.4%3Ac.71G%…
- OncoKB ↗www.oncokb.org/gene/CDK4/R24L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=122871786
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
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 = 0.00). REVEL score = 0.242. BayesDel score = -0.0848312.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV56983700, n = 16 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.