About CDK4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDK4 c.719G>C, p.(Arg240Pro)
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.
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: 1
Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent or extremely rare in large population databases. In gnomAD v2.1, it is observed in 2/251,364 alleles (AF=0.0008%), and in gnomAD v4.1 in 4/1,614,198 alleles (AF=0.00025%), with no homozygotes in either dataset. Both frequencies are well below the 0.1% threshold for PM2.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence support a benign effect: REVEL score is 0.097 (benign), BayesDel score is -0.331 (benign), and SpliceAI predicts no splicing impact (max delta = 0.02). No in silico predictor suggests pathogenicity.
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.
gnomAD v4.1
gnomAD v2.1
Population frequency
4 / 1,614,198 alleles
gnomAD v4.1: 4 / 1,614,198 alleles. Recorded AF 2.47801e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95659e-06; MAF= 0.00080%, 2/251364 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
5 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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. CDK4, an intracellular kinase, is altered by amplification or mutation in various cancer types including soft tissue sarcomas and gliomas.
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
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 · 20 not met · 0 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_000075.4:c.719G>C (p.Arg240Pro) is a missense variant in CDK4 exon 7, currently classified as Uncertain significance by five clinical laboratories in ClinVar (Variation ID: 495534).
This variant is extremely rare in population databases, observed in 2 of 251,364 alleles (AF=0.0008%) in gnomAD v2.1 and 4 of 1,614,198 alleles (AF=0.00025%) in gnomAD v4.1, with no homozygotes, meeting PM2 at supporting strength.
Multiple in silico tools predict a benign effect: REVEL score 0.097, BayesDel score -0.331, and SpliceAI max delta 0.02, meeting BP4 at supporting benign strength.
No variant-specific functional data, de novo observations, case-control data, or segregation data were identified to support other pathogenic or benign criteria.
The variant is in the CDK4 protein kinase domain at residue Arg240, but no statistically significant hotspot or domain-level PM1 specification was found in the current evidence.
Overall, the evidence for pathogenicity (PM2_supporting) is balanced by evidence for a benign effect (BP4_supporting), yielding a classification of Uncertain significance under the generic ACMG/AMP 2015 framework.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent or extremely rare in large population databases. In gnomAD v2.1, it is observed in 2/251,364 alleles (AF=0.0008%), and in gnomAD v4.1 in 4/1,614,198 alleles (AF=0.00025%), with no homozygotes in either dataset. Both frequencies are well below the 0.1% threshold for PM2. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 2/251
- 364 alleles
- AF=7.96e-06
- 0 homozygotes
- gnomAD v4.1: 4/1
- 614
- 198 alleles
- AF=2.48e-06
Sources
BP4 SupportingMultiple lines of computational evidence support a benign effect: REVEL score is 0.097 (benign), BayesDel score is -0.331 (benign), and SpliceAI predicts no splicing impact (max delta = 0.02). No in silico predictor suggests pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.097 (well below 0.5 threshold
- benign)
- BayesDel: -0.330834 (negative score
- SpliceAI: max delta 0.02 (no predicted splicing impact)
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No alternative nucleotide change at the same codon producing the same amino acid change (p.Arg240Pro) has been reported as pathogenic. Details ▾Hide ▴
Still missing
- No same-amino-acid pathogenic comparator variant identified
PS2 No de novo occurrence data is available for this variant. Details ▾Hide ▴
Still missing
- No de novo observation reported
PS3 No variant-specific functional data is available. OncoKB reports Unknown Oncogenic Effect; no experimental studies of NM_000075.4:c.719G>C (p.Arg240Pro) were identified in the literature reviewed. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional evidence curated
Still missing
- No functional studies for p.Arg240Pro or a systematically characterized range that includes residue 240
Sources
PS4 No case-control or cohort data demonstrating enrichment of this variant in affected individuals versus controls is available. ClinVar submissions are all VUS with no phenotype enrichment data. Details ▾Hide ▴
Evidence considered
- ClinVar: 5 clinical laboratories report VUS
- no case-control data
Still missing
- No case-control or affected-enrichment data
Sources
PM1 Residue Arg240 is within the CDK4 protein kinase domain, but the residue is not identified as a statistically significant hotspot (cancerhotspots.org), and no VCEP/CSPEC domain specification or critical-domain literature citation is present in the case materials to support PM1 application. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- exact variant not listed
Still missing
- Arg240 lies in the kinase activation segment
- domain-level PM1 may be applicable if a critical-domain citation is identified
PM6 No de novo observation is reported for this variant. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 No segregation data with the disease phenotype is available for this variant. Details ▾Hide ▴
Still missing
- No segregation analysis reported
PP2 No gene-level missense constraint metric (Z-score, missense depletion ratio) is available in the case materials to assess whether CDK4 has a low rate of benign missense variation. Details ▾Hide ▴
Still missing
- No missense Z-score or constraint metric available for CDK4
PP3 Multiple in silico predictors support a benign effect: REVEL score is 0.097 (well below pathogenicity threshold of ~0.5), BayesDel score is -0.331 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta = 0.02). These data support BP4 rather than PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.097 (benign)
- BayesDel: -0.330834 (benign)
- SpliceAI: max delta 0.02 (no splicing impact)
Sources
PP4 No case-specific phenotype or family history data is available to assess whether the patient's presentation is highly specific for CDK4-related disease. Details ▾Hide ▴
Still missing
- No patient phenotype data in case materials
PP5 ClinVar reports this variant as Uncertain significance with review status 'criteria provided, single submitter' (1-star). Under the global PP5 rule, supporting strength requires a 3-star expert panel review classification of pathogenic/likely pathogenic, which is not met. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- criteria provided
- single submitter
- no expert panel
- 0 expert panel submissions
Sources
BA1 The variant allele frequency in gnomAD (v2.1: 0.0008%, v4.1: 0.00025%) is far below the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 7.96e-06 (0.0008%)
- gnomAD v4.1 AF = 2.48e-06 (0.00025%)
Sources
BS1 The variant allele frequency in gnomAD (v2.1: 0.0008%, v4.1: 0.00025%) is below the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF = 7.96e-06 (0.0008%)
- gnomAD v4.1 AF = 2.48e-06 (0.00025%)
Sources
BS2 No data is available demonstrating observation of this variant in healthy adults at sufficient frequency to meet BS2. Details ▾Hide ▴
Still missing
- No healthy adult observational data for this variant
BS3 No well-established functional studies demonstrate a benign effect of this variant. No experimental data for p.Arg240Pro was identified in the reviewed literature. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence
Still missing
- No functional studies demonstrating benign effect
Sources
BS4 No segregation data is available to evaluate lack of cosegregation with disease. Details ▾Hide ▴
Still missing
- No segregation data available
BP2 No data is available demonstrating this variant observed in trans with a known pathogenic variant. Details ▾Hide ▴
Still missing
- No trans-observation data
BP5 No data is available demonstrating this variant in a case with an established alternative molecular basis for disease. Details ▾Hide ▴
Still missing
- No alternative molecular diagnosis data
BP6 ClinVar reports this variant as Uncertain significance, not benign/likely benign. The review status is 'criteria provided, single submitter' (1-star), which does not meet the 3-star expert panel threshold required for BP6 application. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- 5 submitters
- criteria provided
- single submitter
- no expert panel benign classification
Sources
PS5 The variant has not been reported as a definitive disease-causing mutation in a reputable source; ClinVar reports it as Uncertain significance by all submitters. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS (5 submitters
- review_status: criteria provided
- single submitter)
Sources
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000075.4:c.719G>C is a missense variant (p.Arg240Pro) and does not fall into the generic PVS1 null-variant categories (nonsense, frameshift, or canonical splice site variants). Details ▾Hide ▴
Evidence considered
- PVS1 variant assessment confirms variant_bucket=other
- apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM5 N/APM5 candidate harvesting was unable to confirm classic same-residue comparator variants; no same-position pathogenic missense comparators were identified. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ACDK4 germline disease is associated with missense variants (e.g., R24C/H in familial melanoma), not predominantly truncating variants. BP1 applies when primarily truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- CDK4 pathogenic germline variants are predominantly missense
- known familial melanoma mutations (R24C
- R24H) are missense
BP7 N/AThis is a missense variant (c.719G>C, p.Arg240Pro) located in exon 7. BP7 applies only to synonymous variants or intronic variants outside splice consensus. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- CDK4
- Transcript
- NM_000075.4
- Coding (HGVS c.)
- NM_000075.4:c.719G>C
- Protein (HGVS p.)
- NP_000066.1:p.(Arg240Pro)
- GRCh38
- chr12:57749282 C>G
- GRCh37
- chr12:58143065 C>G
- ClinVar
- 495534
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
4 / 1,614,198 alleles
AF 2.48e-06 · 0 homozygotes
gnomAD v2.1
2 / 251,364 alleles
AF 7.96e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 2.5e-06 · 4 / 1,614,198 alleles · 0 hom
| Middle Eastern1 / 6,062 | 0.00016 |
| Remaining individuals1 / 62,510 | 1.6e-05 |
| South Asian1 / 91,080 | 1.1e-05 |
| European (non-Finnish)1 / 1,180,022 | 8.5e-07 |
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, East Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 8e-06 · 2 / 251,364 alleles · 0 hom
| South Asian1 / 30,616 | 3.3e-05 |
| European (non-Finnish)1 / 113,700 | 8.8e-06 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.47801e-06; MAF= 0.00025%, 4/1614198 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164962; MAF= 0.01650%, 1/6062 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95659e-06; MAF= 0.00080%, 2/251364 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.097
- BayesDel
- -0.331
How the predictions were used
BP4 SupportingMultiple lines of computational evidence support a benign effect: REVEL score is 0.097 (benign), BayesDel score is -0.331 (benign), and SpliceAI predicts no splicing impact (max delta = 0.02). No in silico predictor suggests pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.097 (well below 0.5 threshold
- benign)
- BayesDel: -0.330834 (negative score
- SpliceAI: max delta 0.02 (no predicted splicing impact)
Sources
PP3 Multiple in silico predictors support a benign effect: REVEL score is 0.097 (well below pathogenicity threshold of ~0.5), BayesDel score is -0.331 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta = 0.02). These data support BP4 rather than PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.097 (benign)
- BayesDel: -0.330834 (benign)
- SpliceAI: max delta 0.02 (no splicing impact)
Sources
BP7 N/AThis is a missense variant (c.719G>C, p.Arg240Pro) located in exon 7. BP7 applies only to synonymous variants or intronic variants outside splice consensus. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.097. BayesDel score = -0.330834.
4 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015This is the ACMG/AMP 2015 standards and guidelines for interpreting sequence variants. It provides the methodological framework for variant classification but does not discuss the CDK4 c.719G>C (p.Arg240Pro) variant.Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline for referral indications for cancer predisposition assessment. Discusses general referral criteria for cancer genetic counseling but does not mention the CDK4 c.719G>C (p.Arg240Pro) variant.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ Cancer Genetics Risk Assessment and Counseling summary. A general cancer genetics educational resource; does not mention the CDK4 c.719G>C (p.Arg240Pro) variant.Does not name this variant
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PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ Genetics of Skin Cancer summary. A general educational resource on skin cancer genetics; does not mention the CDK4 c.719G>C (p.Arg240Pro) variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
4 / 1,614,198 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
5 Uncertain significance
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/variation/495534/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-58143065-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-57749282-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/12-57749282-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000075.4%3Ac.719G…
- OncoKB ↗www.oncokb.org/gene/CDK4/R240P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDK4+c.719G%3EC
- 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 v4.1
This variant is present in gnomAD v4.1 (AF= 2.47801e-06; MAF= 0.00025%, 4/1614198 alleles, homozygotes = 0) and has highest observed frequency in the Middle Eastern population (AF= 0.000164962; MAF= 0.01650%, 1/6062 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 7.95659e-06; MAF= 0.00080%, 2/251364 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.26627e-05; MAF= 0.00327%, 1/30616 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 495534)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.097. BayesDel score = -0.330834.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. CDK4, an intracellular kinase, is altered by amplification or mutation in various cancer types including soft tissue sarcomas and gliomas.
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.