About CDK4
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
CDK4 c.823A>T, p.(Met275Leu)
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: 2
Benign evidence criteria: 1
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
NM_000075.4:c.823A>T is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-6 (1/251,446 alleles), gnomAD v4.1 AF=1.86e-6 (3/1,612,194 alleles; grpmax FAF=6.8e-7), and absent from gnomAD-Canada. All frequencies are well below the 0.1% PM2 threshold.
PP2Supporting
PP2 · supporting
CDK4 is a gene in which missense variants are a well-established mechanism of disease (e.g., R24C/H in hereditary melanoma) and which has a low rate of benign missense variation in the general population. PP2 is met at supporting level.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.197 (below 0.5 benign threshold), BayesDel score is -0.0628 (negative, consistent with benign), and SpliceAI max delta score is 0.00 (no predicted splicing alteration).
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, PP2 supporting, BP4 supporting benign; combination = 2 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
3 / 1,612,194 alleles
gnomAD v4.1: 3 / 1,612,194 alleles. Recorded AF 1.86082e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.977e-06; MAF= 0.00040%, 1/251446 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79198e-06; MAF= 0.00088%, 1/113740 alleles, homozygotes = 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
3 reported laboratory submissions
3 Uncertain significance.
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.
29 criteria with recorded statuses: 3 met · 20 not met · 0 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
NM_000075.4:c.823A>T (p.Met275Leu) is a missense variant in CDK4, a gene in which missense variants are a known mechanism of autosomal dominant hereditary melanoma.
This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-6 (1/251,446 alleles) and gnomAD v4.1 AF=1.86e-6 (3/1,612,194 alleles; grpmax FAF=6.8e-7), satisfying PM2 at supporting level.
The variant meets PP2 at supporting level: CDK4 has a low rate of benign missense variation and missense variants are a well-established disease mechanism (e.g., R24C/H in hereditary melanoma).
Multiple lines of in silico evidence support a benign interpretation: REVEL score 0.197 (<0.5), BayesDel score -0.0628 (negative), and SpliceAI max delta 0.00 (no splicing impact), satisfying BP4 at supporting benign level.
This variant has been reported in ClinVar as Uncertain Significance by three clinical laboratories (Variation ID 141405). No functional studies, segregation data, case-control comparisons, or de novo observations are available for this variant.
Two supporting pathogenic criteria (PM2, PP2) and one supporting benign criterion (BP4) net to one supporting pathogenic criterion, resulting in a final classification of Variant of Uncertain Significance (VUS) under the generic ACMG/AMP 2015 framework.
No criteria match.
Met · 3
PM2 SupportingNM_000075.4:c.823A>T is present at extremely low frequency in population databases: gnomAD v2.1 AF=3.98e-6 (1/251,446 alleles), gnomAD v4.1 AF=1.86e-6 (3/1,612,194 alleles; grpmax FAF=6.8e-7), and absent from gnomAD-Canada. All frequencies are well below the 0.1% PM2 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/251
- 446 alleles (AF=3.98e-6
- 0.00040%)
- gnomAD v4.1: 3/1
- 612
- 194 alleles (AF=1.86e-6
- 0.00019%
- grpmax FAF=6.8e-7)
- Absent from gnomAD-Canada v1.0
- All frequencies <0.1% PM2 threshold
- no homozygotes observed.
Sources
PP2 SupportingCDK4 is a gene in which missense variants are a well-established mechanism of disease (e.g., R24C/H in hereditary melanoma) and which has a low rate of benign missense variation in the general population. PP2 is met at supporting level. Details ▾Hide ▴
Evidence considered
- CDK4 is a recognized hereditary melanoma predisposition gene with pathogenic missense variants as the primary disease mechanism.
- Low frequency of missense variants in gnomAD supports low benign missense variation rate.
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.197 (below 0.5 benign threshold), BayesDel score is -0.0628 (negative, consistent with benign), and SpliceAI max delta score is 0.00 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
- REVEL: 0.197 (benign range
- <0.5)
- BayesDel: -0.0628 (negative score
- favors benign)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No alternative nucleotide change at codon 275 yielding the same amino acid substitution (p.Met275Leu) has been reported as pathogenic in ClinVar, COSMIC, or the literature. No same-residue comparator variants were identified in the PM5 candidate search. Details ▾Hide ▴
Evidence considered
- No pathogenic variant with the same amino acid change (M275L) via a different nucleotide substitution identified.
Sources
PS2 No de novo occurrence of NM_000075.4:c.823A>T with confirmed maternity and paternity has been reported in the literature or public databases. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in PubMed or ClinVar for this variant.
Still missing
- No trio or duo sequencing data available for this variant.
PS3 No well-established functional studies have been performed for the p.Met275Leu variant. No kinase activity, binding, or cellular proliferation assays specific to this variant were identified. Details ▾Hide ▴
Evidence considered
- OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific functional data.
- No functional publications for p.Met275Leu identified.
Still missing
- No experimental functional characterization of p.Met275Leu (e.g.
- kinase assay
- p16 binding
- proliferation).
Sources
PS4 No case-control study comparing the prevalence of NM_000075.4:c.823A>T in affected individuals versus controls has been published. The variant is observed at extremely low frequency in gnomAD (1/251,446 in v2.1; 3/1,612,194 in v4.1) but this alone is insufficient to satisfy PS4 without a statistically significant odds ratio. Details ▾Hide ▴
Evidence considered
- Variant is present in gnomAD at extremely low frequency but no case-control comparison exists.
Still missing
- No case-control or association study for this variant.
Sources
PM1 Codon 275 resides in the C-terminal extension beyond the core kinase domain (residues ~6-295). Cancer Hotspots does not identify residue 275 as a statistically significant hotspot. Known CDK4 pathogenic missense variants cluster at codon 24 (R24C/H) in the N-terminal domain. Details ▾Hide ▴
Evidence considered
- Codon 275 is not in a recognized mutational hotspot or critical functional domain.
- Cancer Hotspots: residue not significant
- exact variant not listed.
PM5 No pathogenic missense variant at codon 275 via a different amino acid substitution has been identified. PM5 candidate harvesting found zero comparator variants at this residue. Details ▾Hide ▴
Evidence considered
- No pathogenic or likely pathogenic missense variant at codon 275 identified in ClinVar or literature.
PM6 No assumed de novo occurrence of NM_000075.4:c.823A>T (without confirmation of paternity and maternity) has been reported. Details ▾Hide ▴
Evidence considered
- No publication describing de novo observation of this variant identified.
Still missing
- No trio or duo sequencing data for this variant.
PP1 No co-segregation data for NM_000075.4:c.823A>T with disease in affected families has been reported. Details ▾Hide ▴
Evidence considered
- No family-based segregation studies for this variant identified.
Still missing
- No genotype-phenotype linkage data in families.
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.197 (below 0.5 threshold), BayesDel score is -0.0628 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta=0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.197 (<0.5 threshold for pathogenicity)
- BayesDel: -0.0628 (negative score
- favors benign)
- SpliceAI: max delta 0.00 (no splicing impact predicted)
Sources
PP4 No patient phenotype or family history data are available for adjudication. 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 proband phenotype or family history information available.
Still missing
- No clinical phenotype data for the individual(s) carrying this variant.
PP5 No reputable source has reported NM_000075.4:c.823A>T as pathogenic. ClinVar classifies it as Uncertain Significance (Variation ID 141405). None of the associated ClinVar PMIDs (25394175, 26389258, 26389333, 28492532) mention this specific variant. Details ▾Hide ▴
Evidence considered
- ClinVar VUS classification from 3 clinical laboratories.
- No reputable source (expert panel
- professional guideline) reports the variant as pathogenic.
Sources
BA1 The maximum allele frequency of NM_000075.4:c.823A>T in gnomAD is 8.79e-6 (v2.1 NFE) and 2.55e-6 (v4.1 NFE), both far below the BA1 threshold of 1% (0.01). Details ▾Hide ▴
Evidence considered
- Highest subpopulation AF: 8.79e-6 (gnomAD v2.1 NFE) and 2.55e-6 (gnomAD v4.1 NFE)
- both <<1% BA1 threshold.
Sources
BS1 The maximum allele frequency of NM_000075.4:c.823A>T (8.79e-6 in gnomAD v2.1; 2.55e-6 in gnomAD v4.1) is well below the BS1 threshold of 0.3% (0.003) for non-VCEP adjudication. Details ▾Hide ▴
Evidence considered
- Highest subpopulation AF: 8.79e-6 (v2.1) and 2.55e-6 (v4.1)
- both <<0.3% BS1 threshold.
Sources
BS2 Although NM_000075.4:c.823A>T is observed in gnomAD (3 heterozygous carriers in v4.1), CDK4-associated hereditary melanoma has incomplete penetrance and adult onset. BS2 requires observation in a healthy adult for a disorder with full penetrance expected at an early age; melanoma predisposition does not meet this threshold. Details ▾Hide ▴
Evidence considered
- 3 heterozygous carriers in gnomAD v4.1
- but CDK4 melanoma risk has reduced penetrance and adult onset
- not meeting strict BS2 requirements.
Sources
BS3 No well-established functional studies demonstrating no deleterious effect of the p.Met275Leu variant have been published. Details ▾Hide ▴
Evidence considered
- No variant-specific functional assays demonstrating benign effect identified.
Still missing
- No experimental evidence for normal protein function.
BS4 No data demonstrating lack of co-segregation of NM_000075.4:c.823A>T with disease in affected families are available. Details ▾Hide ▴
Evidence considered
- No non-segregation data in families identified.
Still missing
- No data on unaffected individuals carrying the variant in affected families.
BP2 No evidence of NM_000075.4:c.823A>T observed in trans with a pathogenic variant for CDK4. CDK4-associated disease is autosomal dominant; no recessive CDK4 phenotype is known. Details ▾Hide ▴
Evidence considered
- No reports of biallelic CDK4 variants
- autosomal dominant inheritance.
BP5 No evidence that NM_000075.4:c.823A>T was found in a case with an alternate molecular basis for disease. No such clinical data are available. Details ▾Hide ▴
Evidence considered
- No case with an alternate molecular explanation for the phenotype identified.
Still missing
- No clinical context for proband(s) carrying this variant.
BP6 No reputable source has reported NM_000075.4:c.823A>T as benign. ClinVar classifies it as Uncertain Significance (Variation ID 141405), not benign or likely benign. Details ▾Hide ▴
Evidence considered
- ClinVar classification is VUS
- no reputable source asserts benign status.
Sources
clinvar ↗28492532
PS5 No reputable source has reported NM_000075.4:c.823A>T as pathogenic. ClinVar classifies this variant as Uncertain Significance (3 clinical laboratories, criteria provided single submitter). Details ▾Hide ▴
Evidence considered
- ClinVar classification is VUS (Variation ID 141405)
- no expert panel or reputable source has asserted pathogenicity.
Sources
clinvar ↗28492532
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000075.4:c.823A>T is a missense variant (p.Met275Leu) and does not fall into any null-variant bucket (nonsense, frameshift, canonical ±1/2 splice consensus) required for PVS1 per the ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution at c.823
- variant_bucket=other
- not a null variant.
Sources
PM3 N/APM3 applies to recessive disorders (variant detected in trans with a pathogenic variant). CDK4-associated disease is autosomal dominant; no recessive CDK4 phenotype is known. Details ▾Hide ▴
Evidence considered
- CDK4 disease is autosomal dominant.
- No reports of biallelic CDK4 mutations.
PM4 N/APM4 applies to protein length changes due to in-frame deletions/insertions, stop-loss variants, or variants disrupting the initiation codon. NM_000075.4:c.823A>T is a single nucleotide missense substitution with no protein length alteration. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- no protein length change.
BP1 N/ABP1 applies to missense variants in genes where primarily truncating variants cause disease. CDK4 hereditary melanoma is primarily caused by missense variants (gain-of-function, e.g., R24C/H), not truncating variants. BP1 is therefore not applicable. Details ▾Hide ▴
Evidence considered
- CDK4 disease mechanism is missense (gain-of-function)
- not truncating loss-of-function.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. NM_000075.4:c.823A>T is a single nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
- Variant is a substitution
- not an in-frame indel.
BP7 N/ABP7 applies to synonymous variants not predicted to affect splicing. NM_000075.4:c.823A>T is a missense variant (p.Met275Leu), not synonymous. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Met275Leu)
- not synonymous.
Identifiers
- Gene
- CDK4
- Transcript
- NM_000075.4
- Coding (HGVS c.)
- NM_000075.4:c.823A>T
- Protein (HGVS p.)
- NP_000066.1:p.(Met275Leu)
- GRCh38
- chr12:57748614 T>A
- GRCh37
- chr12:58142397 T>A
- ClinVar
- 141405
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
3 / 1,612,194 alleles
AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1
1 / 251,446 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,612,194 alleles · 0 hom · FAF 6.8e-07
| European (non-Finnish)3 / 1,178,216 | 2.5e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 4e-06 · 1 / 251,446 alleles · 0 hom
| European (non-Finnish)1 / 113,740 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.86082e-06; MAF= 0.00019%, 3/1612194 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54622e-06; MAF= 0.00025%, 3/1178216 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.977e-06; MAF= 0.00040%, 1/251446 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79198e-06; MAF= 0.00088%, 1/113740 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.197
- BayesDel
- -0.063
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.197 (below 0.5 benign threshold), BayesDel score is -0.0628 (negative, consistent with benign), and SpliceAI max delta score is 0.00 (no predicted splicing alteration). Details ▾Hide ▴
Evidence considered
- REVEL: 0.197 (benign range
- <0.5)
- BayesDel: -0.0628 (negative score
- favors benign)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.197 (below 0.5 threshold), BayesDel score is -0.0628 (negative, favoring benign), and SpliceAI predicts no splicing impact (max delta=0.00). Details ▾Hide ▴
Evidence considered
- REVEL: 0.197 (<0.5 threshold for pathogenicity)
- BayesDel: -0.0628 (negative score
- favors benign)
- SpliceAI: max delta 0.00 (no splicing impact predicted)
Sources
BP7 N/ABP7 applies to synonymous variants not predicted to affect splicing. NM_000075.4:c.823A>T is a missense variant (p.Met275Leu), not synonymous. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Met275Leu)
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.197. BayesDel score = -0.0628374.
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 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. · 2015No paper-specific finding is recorded.
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
-
PMID 26389333 ↗Genetics of Skin Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002No paper-specific finding is recorded.
-
PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3 / 1,612,194 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
3 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/141405/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/12-58142397-T-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr12-57748614-T-A?dataset=gn…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000075.4%3Ac.823A…
- OncoKB ↗www.oncokb.org/gene/CDK4/M275L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=CDK4+c.823A%3ET
- 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= 1.86082e-06; MAF= 0.00019%, 3/1612194 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54622e-06; MAF= 0.00025%, 3/1178216 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.977e-06; MAF= 0.00040%, 1/251446 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.79198e-06; MAF= 0.00088%, 1/113740 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 141405)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.197. BayesDel score = -0.0628374.
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.