About FBXW7
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FBXW7 c.1514G>T, p.(Arg505Leu)
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: 3
Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Supporting
PS3 · supporting
Functional data from PMID:17646409 demonstrate that mutation of Arg505 (specifically R505C) in the FBXW7 WD40 substrate-recognition domain disrupts binding to NOTCH1 intracellular domain (NICD) and impairs MYC degradation, producing a dominant-negative allele. The exact variant (R505L) was not directly tested and the study characterized only three specific arginine residues rather than a systematic range, limiting PS3 to supporting strength under the calibration framework.
PM1Moderate
PM1 · moderate
The variant affects Arg505, a critical arginine residue within the WD40 beta-propeller substrate-recognition domain of FBXW7. PMID:17646409 demonstrates that mutations at Arg505 (along with Arg465 and Arg479) in this domain disrupt substrate binding to NOTCH1 and MYC, and the residue is identified as a statistically significant cancer hotspot (cancerhotspots.org). PM1 is applied at moderate strength based on location in a well-characterized functional domain without benign variation.
PM2Supporting
PM2 · supporting
The variant is extremely rare in population databases. gnomAD v4.1 reports a single allele among 1,613,302 total alleles (AF = 6.2e-07; MAF = 0.00006%) in the European (non-Finnish) population, with zero homozygotes. The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0. This is well below the PM2 threshold of 0.1% under generic ACMG/AMP.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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: PS3 supporting, PM1 moderate, PM2 supporting; combination = 1 moderate + 2 supporting, 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
1 / 1,613,302 alleles
gnomAD v4.1: 1 / 1,613,302 alleles. Recorded AF 6.19847e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.130 maximum delta
Recorded SpliceAI maximum delta score: 0.130. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
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: Loss-of-function; curated oncogenicity label: Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
36 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV55908371, n = 36 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.
26 criteria with recorded statuses: 3 met · 11 not met · 9 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_033632.3:c.1514G>T (p.Arg505Leu) is a missense variant in exon 10 of FBXW7, affecting a critical arginine residue in the WD40 substrate-recognition domain.
The variant is extremely rare in population databases, with a single heterozygous observation among 1,613,302 alleles in gnomAD v4.1 (AF = 6.2e-07), meeting PM2 at supporting strength.
The variant is located at Arg505 in the WD40 beta-propeller domain, a well-characterized functional domain critical for substrate recognition and ubiquitination. Mutations at this residue have been shown to disrupt NOTCH1 and MYC binding (PMID:17646409), and the residue is a statistically significant cancer hotspot, meeting PM1 at moderate strength.
Functional studies of an R505C substitution at the same residue demonstrate that mutation of Arg505 impairs FBXW7 substrate binding, producing a dominant-negative allele. While the exact variant (R505L) was not directly tested and the study characterized only three specific arginine residues rather than a systematic range, the functional data at the same position supports a deleterious effect, meeting PS3 at supporting strength.
Applying the generic ACMG/AMP 2015 final classification combination rules (PMID:25741868), one moderate criterion (PM1) plus two supporting criteria (PM2, PS3) is insufficient to reach likely pathogenic classification, which requires at minimum either two moderate criteria or one moderate plus four supporting criteria. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 3
PS3 SupportingFunctional data from PMID:17646409 demonstrate that mutation of Arg505 (specifically R505C) in the FBXW7 WD40 substrate-recognition domain disrupts binding to NOTCH1 intracellular domain (NICD) and impairs MYC degradation, producing a dominant-negative allele. The exact variant (R505L) was not directly tested and the study characterized only three specific arginine residues rather than a systematic range, limiting PS3 to supporting strength under the calibration framework. Details ▾Hide ▴
Evidence considered
- PMID:17646409: R505C mutation in FBXW7 WD40 domain abolishes NICD binding and MYC degradation in co-immunoprecipitation and ubiquitination assays.
- Same residue (Arg505) different substitution
- functional effect direction is clearly damaging and consistent with loss-of-function mechanism.
Still missing
- Exact variant (R505L) was not directly assayed
- functional data is from R505C
- a different substitution at the same residue.
- No systematic tiling or saturation mutagenesis of the WD40 domain was performed — only three arginine residues tested.
Sources
PM1 ModerateThe variant affects Arg505, a critical arginine residue within the WD40 beta-propeller substrate-recognition domain of FBXW7. PMID:17646409 demonstrates that mutations at Arg505 (along with Arg465 and Arg479) in this domain disrupt substrate binding to NOTCH1 and MYC, and the residue is identified as a statistically significant cancer hotspot (cancerhotspots.org). PM1 is applied at moderate strength based on location in a well-characterized functional domain without benign variation. Details ▾Hide ▴
Evidence considered
- PMID:17646409: The WD40 domain (exons 7–11) is the substrate-binding domain
- Arg505 is one of three key arginine residues critical for substrate recognition.
- cancerhotspots.org: Residue is in a statistically significant hotspot.
- OncoKB: Classified as Oncogenic with Loss-of-function effect.
Sources
PM2 SupportingThe variant is extremely rare in population databases. gnomAD v4.1 reports a single allele among 1,613,302 total alleles (AF = 6.2e-07; MAF = 0.00006%) in the European (non-Finnish) population, with zero homozygotes. The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0. This is well below the PM2 threshold of 0.1% under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1/1
- 613
- 302 alleles (AF = 6.2e-07)
- 0 homozygotes
- highest in NFE (1/1
- 179
- 522).
- Absent from gnomAD v2.1 and gnomAD-Canada v1.0.
Sources
Not met · 11 · evaluated, threshold not reached
PS1 No pathogenic or likely pathogenic variant with the same amino acid change (p.Arg505Leu) has been identified in ClinVar or the literature. PS1 requires an established pathogenic variant resulting in the identical amino acid change via a different nucleotide alteration. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar
- no same-amino-acid pathogenic comparator exists.
Sources
PM5 No different pathogenic missense variant at the same amino acid position (Arg505) has been identified in ClinVar with a pathogenic or likely pathogenic classification. While PMID:17646409 reports an R505C mutation in somatic T-ALL cell lines, this is not a ClinVar-classified germline pathogenic variant and does not satisfy PM5 requirements under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting returned zero ClinVar comparator variants at the same residue.
- PMID:17646409 reports somatic R505C
- not a ClinVar-classified germline variant.
Sources
pm5_candidatesclinvar ↗
PP3 In silico predictions do not provide multiple converging lines of evidence for a deleterious effect. REVEL score of 0.601 is borderline and falls below the more stringent threshold of 0.75. BayesDel score of 0.235 is below the standard damaging threshold of 0.27 (noAF version). SpliceAI predicts no splicing impact (max delta = 0.13). Only one of three computational tools (REVEL) provides equivocal support, which is insufficient for PP3 under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- REVEL: 0.601 (borderline
- below stringent 0.75 threshold).
- BayesDel: 0.235 (below 0.27 damaging threshold).
- SpliceAI: max delta 0.13 (no predicted splice impact).
Sources
PP5 This variant is absent from ClinVar. PP5 requires a pathogenic or likely pathogenic classification from a reputable source (3-star expert panel or equivalent). No such classification exists for this variant. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar
- no reputable source has classified it.
Sources
BA1 The gnomAD v4.1 allele frequency of 6.2e-07 (0.00006%) is far below the BA1 threshold of 1%. This variant is too rare in the general population to qualify as a common benign polymorphism. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 6.2e-07 (0.00006%)
- well below 1% BA1 threshold.
Sources
BS1 The gnomAD v4.1 allele frequency of 6.2e-07 (0.00006%) is far below the BS1 threshold of 0.3%. This variant is too rare to be considered a benign polymorphism with frequency exceeding disease prevalence. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF = 6.2e-07 (0.00006%)
- well below 0.3% BS1 threshold.
Sources
BS3 The only available functional study (PMID:17646409) demonstrates that mutations at Arg505 in FBXW7 disrupt substrate binding and produce a dominant-negative effect, consistent with a damaging rather than benign functional impact. No well-established functional studies show no deleterious effect. Details ▾Hide ▴
Evidence considered
- PMID:17646409: R505 mutations impair FBXW7 function
- no evidence of normal function.
Sources
BP1 FBXW7 germline disease is not caused exclusively by truncating variants. Multiple publications (PMID:35395208, PMID:42111496) establish that missense variants clustering in the WD40 domain are a common mechanism of FBXW7-related neurodevelopmental disorder. BP1 is only applicable when a gene's disease mechanism is primarily through truncating variants. Details ▾Hide ▴
Evidence considered
- PMID:35395208: Germline FBXW7 missense variants cause neurodevelopmental syndrome.
- PMID:42111496: Reported germline variants include missense
- frameshift
- and splice-site
- with majority clustering in WD40 domain.
BP4 While SpliceAI predicts no splicing impact (max delta = 0.13), the REVEL score of 0.601 suggests a potential deleterious effect on protein function. BP4 requires multiple lines of computational evidence to suggest no impact on gene or gene product, which is not satisfied when one tool suggests a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.13 (no splice impact).
- REVEL: 0.601 (suggests potential deleterious effect
- inconsistent with BP4).
- BayesDel: 0.235 (below damaging threshold but not clearly benign).
Sources
BP6 This variant is absent from ClinVar. BP6 requires a benign or likely benign classification from a reputable source (3-star expert panel or equivalent). No such classification exists. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar
- no reputable source has classified it as benign.
Sources
PS5 No alternative nucleotide change at the same position resulting in the same amino acid change (p.Arg505Leu) has been established as pathogenic. PS5 requires a proven pathogenic variant producing the same missense change through a different nucleotide substitution. Details ▾Hide ▴
Evidence considered
- This variant is absent from ClinVar
- no same-amino-acid alternative nucleotide comparator exists.
Sources
Not assessed · 9 · no assessment recorded
PS2 No de novo data are available for this variant. PS2 requires confirmation that the variant occurred de novo with both maternity and paternity confirmed. Details ▾Hide ▴
Still missing
- No de novo testing data available for this variant.
PS4 The variant is absent from ClinVar and no case-control or case-series data are available. PS4 requires significantly increased prevalence in affected individuals compared with controls. Details ▾Hide ▴
Still missing
- No case-control or cohort data available.
PM6 No de novo reports are available for this variant. PM6 requires confirmation of a de novo occurrence with maternity and paternity confirmed, without confirmation through any other means. Details ▾Hide ▴
Still missing
- No de novo testing data available.
PP1 No segregation data are available for this variant. PP1 requires co-segregation of the variant with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
PP2 No gene-level missense constraint metric (HCI prior, gnomAD missense Z-score, or observed/expected ratio) is available for FBXW7. While FBXW7 germline missense variants are a known disease mechanism (PMID:35395208), PP2 requires explicit constraint data demonstrating a low rate of benign missense variation, which is not available in the case materials. Details ▾Hide ▴
Evidence considered
- FBXW7 germline missense variants are a known mechanism for neurodevelopmental syndrome (PMID:35395208).
- HCI prior not available for FBXW7
- no gnomAD missense constraint metric in evidence.
Still missing
- No gene-level missense constraint data
- gnomAD missense Z-score or o/e ratio would be needed to apply PP2.
PP4 No specific phenotypic data are available for this variant. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient-specific phenotypic data available.
BS2 No data are available on observation of this variant in healthy adults. BS2 requires observation in a healthy adult individual for a recessive, X-linked, or fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No data on observation in healthy adult individuals.
BS4 No segregation data are available to evaluate lack of co-segregation with disease. BS4 requires observation that the variant does not segregate with disease in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP5 No data are available on observation of this variant in a case with an alternate molecular basis for disease. BP5 requires the variant to be found in a case with a clear alternate cause of disease. Details ▾Hide ▴
Still missing
- No data on cases with alternate molecular basis.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_033632.3:c.1514G>T is a missense variant (p.Arg505Leu), not a null variant. The variant falls outside the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- PVS1 decision tree does not apply to missense variants.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP2 N/ANo observation of this variant in trans with a known pathogenic FBXW7 variant. BP2 requires observation in trans with a dominant pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant in a recessive disorder. Details ▾Hide ▴
Evidence considered
- No in trans or in cis observations available.
BP7 N/ANM_033632.3:c.1514G>T is a missense variant (p.Arg505Leu), not a synonymous variant. BP7 applies exclusively to synonymous variants with no predicted splicing impact and non-conserved nucleotides. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 only applies to synonymous variants.
Identifiers
- Gene
- FBXW7
- Transcript
- NM_033632.3
- Coding (HGVS c.)
- NM_033632.3:c.1514G>T
- Protein (HGVS p.)
- NP_361014.1:p.(Arg505Leu)
- GRCh38
- chr4:152326136 C>A
- GRCh37
- chr4:153247288 C>A
- COSMIC
- COSV55908371
Gene diagram
Every interpreted variant in FBXW7, mapped onto the exon structure of NM_033632.3. Select a row to find it on the plot.
FBXW7NM_033632.3
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 FBXW7
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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
1 / 1,613,302 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,302 alleles · 0 hom
| European (non-Finnish)1 / 1,179,522 | 8.5e-07 |
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.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19847e-07; MAF= 0.00006%, 1/1613302 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47801e-07; MAF= 0.00008%, 1/1179522 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.601
- BayesDel
- 0.236
How the predictions were used
PP3 In silico predictions do not provide multiple converging lines of evidence for a deleterious effect. REVEL score of 0.601 is borderline and falls below the more stringent threshold of 0.75. BayesDel score of 0.235 is below the standard damaging threshold of 0.27 (noAF version). SpliceAI predicts no splicing impact (max delta = 0.13). Only one of three computational tools (REVEL) provides equivocal support, which is insufficient for PP3 under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- REVEL: 0.601 (borderline
- below stringent 0.75 threshold).
- BayesDel: 0.235 (below 0.27 damaging threshold).
- SpliceAI: max delta 0.13 (no predicted splice impact).
Sources
BP4 While SpliceAI predicts no splicing impact (max delta = 0.13), the REVEL score of 0.601 suggests a potential deleterious effect on protein function. BP4 requires multiple lines of computational evidence to suggest no impact on gene or gene product, which is not satisfied when one tool suggests a deleterious effect. Details ▾Hide ▴
Evidence considered
- SpliceAI: max delta 0.13 (no splice impact).
- REVEL: 0.601 (suggests potential deleterious effect
- inconsistent with BP4).
- BayesDel: 0.235 (below damaging threshold but not clearly benign).
Sources
BP7 N/ANM_033632.3:c.1514G>T is a missense variant (p.Arg505Leu), not a synonymous variant. BP7 applies exclusively to synonymous variants with no predicted splicing impact and non-conserved nucleotides. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 only applies to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13). REVEL score = 0.601. BayesDel score = 0.235507.
1 paper record listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.
Cited in the classification
-
PMID 17646409 ↗FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.Demonstrates that FBW7 (FBXW7) R505C mutations in the WD40 domain disrupt binding to NOTCH1 intracellular domain (NICD) and impair MYC degradation in T-ALL cell lines. The R505C mutant acts as a dominant-negative allele. The paper reports R505C (p.Arg505Cys, NM_033632:c.1513C>T) in Jurkat, HSB2, and PEER T-ALL cell lines, but does not report the R505L (c.1514G>T) variant under review.→ PS3 → PM1 Does not name this variant
Source detail
Each of the seven cell lines with increased levels of NICD but without C-terminal truncating mutations in NOTCH1 (RPMI8402, CEM, BE13, DU528, HSB2, Jurkat, and PEER) harbored either a mutation in FBW7 or homozygous deletion of the gene.
Location Table I (T-ALL cell line FBW7 mutations); Results section 'FBW7 is mutated in T-ALL cell lines and primary samples'; Methods section 'Plasmids and transient transfections' (R505C mutant construction)
Context Co-immunoprecipitation, ubiquitination assays, and pulse-chase experiments in 293a and K562 cells; T-ALL cell lines Jurkat (R505C heterozygous) and HSB2 (R505C heterozygous)
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,613,302 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.130
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_033632.3%3Ac.1514G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-153247288-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-152326136-C-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-152326136-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_033632.3%3Ac.1514…
- OncoKB ↗www.oncokb.org/gene/FBXW7/R505L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=210673532
- 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= 6.19847e-07; MAF= 0.00006%, 1/1613302 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47801e-07; MAF= 0.00008%, 1/1179522 alleles, homozygotes = 0).
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 = 0.13). REVEL score = 0.601. BayesDel score = 0.235507.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55908371, n = 36 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.