About FBXW7
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FBXW7 c.1697G>T, p.(Trp566Leu)
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: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
This variant is absent from all queried population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (whole genomes). Allele count is zero across all populations, consistent with a rare variant well below the PM2 frequency threshold of 0.1%.
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: PM2 supporting; combination = 1 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.120 maximum delta
Recorded SpliceAI maximum delta score: 0.120. 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 did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FBXW7, a tumor suppressor involved in protein degradation, is inactivated by mutation in various cancer types, most frequently in endometrial and colo
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
2 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV99662097, n = 2 times).
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: 1 met · 22 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_033632.3:c.1697G>T (p.Trp566Leu) is a missense variant in exon 11 of FBXW7, affecting the WD40 repeat domain critical for substrate recognition. The variant is completely absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada (PM2_Supporting).
FBXW7 germline loss-of-function and missense variants are established causes of an autosomal dominant neurodevelopmental syndrome with Wilms tumor predisposition (PMID:35395208). The variant alters a highly conserved tryptophan residue within the WD40 domain where pathogenic missense variants cluster (PMID:42111496), though no formal VCEP domain specification exists. The variant has been reported twice in somatic cancers (COSMIC COSV99662097), consistent with a role in tumorigenesis.
REVEL predicts a damaging score of 0.863, though BayesDel (0.424) does not reach the damaging threshold, and no variant-specific functional studies were identified. Computational evidence alone is insufficient to meet PP3.
No ClinVar entries, no published variant-specific functional studies, no segregation or de novo data, and no case-control evidence exist for this variant. The variant remains unclassified in all major clinical databases.
No criteria match.
Met · 1
PM2 SupportingThis variant is absent from all queried population databases: gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (whole genomes). Allele count is zero across all populations, consistent with a rare variant well below the PM2 frequency threshold of 0.1%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AC=0)
- Absent from gnomAD v4.1 (AC=0)
- Absent from gnomAD-Canada v1.0 (AC=0)
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No evidence of a different nucleotide change at codon 566 (Trp) producing the same amino acid substitution (p.Trp566Leu) that has been established as pathogenic. This variant is absent from ClinVar and no literature reports a same-amino-acid comparator. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no literature identifying a pathogenic comparator at the same residue with same amino acid change
Still missing
- No ClinVar or literature entries for any variant producing p.Trp566Leu via an alternate nucleotide change
Sources
PS2 No de novo occurrence data are available for this variant. No proband or trio sequencing data were identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar with no submitted de novo observations
Still missing
- No proband or parental testing data available
Sources
PS3 No well-established functional studies evaluating the specific impact of p.Trp566Leu on FBXW7 protein function were identified. OncoKB classifies this variant as Unknown Oncogenic Effect with no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies identified in curated databases or literature
Still missing
- No functional studies (enzymatic
- subcellular localization
- or substrate degradation assays) for this specific variant
Sources
PS4 No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals compared to controls. The variant is absent from ClinVar with no clinical assertions. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar and all gnomAD population databases
- no affected-vs-control comparison possible
Still missing
- No affected proband cohort data for this variant
Sources
PM1 p.Trp566Leu lies within the WD40 repeat domain of FBXW7, a region critical for substrate recognition and frequently mutated in disease. However, no formal CSPEC/VCEP framework defines domain boundaries for PM1 application in FBXW7, and the variant does not lie in a statistically significant cancer hotspot (CancerHotspots.org). Without domain-level specification, PM1 cannot be confidently applied under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- WD40 domain is functionally critical per literature
- variant not in a statistically significant hotspot
- no VCEP domain criteria for FBXW7
Still missing
- No VCEP/CSPEC domain specification for FBXW7 PM1 boundaries
PM6 No de novo occurrence data are available for this variant. No trio-based or parental confirmation sequencing data were identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no de novo reports in literature
Still missing
- No proband or parental testing data available
Sources
PP1 No cosegregation data are available for this variant. No family studies or pedigree analyses were identified. Details ▾Hide ▴
Evidence considered
- No family segregation data available
Still missing
- No multigenerational pedigree or cosegregation analysis for this variant
PP2 Insufficient data to establish that FBXW7 has a low rate of benign missense variation as required for PP2. While the gene is constrained and pathogenic missense variants are reported in the literature (primarily in the WD40 domain), no gnomAD missense Z-score or constraint metrics are available for formal PP2 application. Details ▾Hide ▴
Evidence considered
- FBXW7 known to harbor pathogenic missense variants
- but formal constraint metrics (missense Z-score) not available for PP2 assessment
Still missing
- No gnomAD missense constraint metrics available for FBXW7
PP3 In silico predictions provide only partial support for a deleterious effect. REVEL predicts a damaging score of 0.863 (above the 0.5 threshold), but BayesDel yields a score of 0.424 (below typical damaging thresholds). SpliceAI predicts no significant splice impact (max delta = 0.12). Without at least two concordant in silico predictors supporting pathogenicity, PP3 is not met under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- REVEL=0.863 (damaging)
- BayesDel=0.424 (borderline/not damaging)
- SpliceAI max delta=0.12 (no splice impact)
Still missing
- Discordant in silico predictions
- REVEL damaging but BayesDel does not corroborate
Sources
PP4 No proband phenotype or clinical data are available for this variant. The variant is absent from ClinVar with no associated clinical assertions or phenotype descriptions. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data or disease-specific presentation documented for this variant
Still missing
- No proband phenotype information available
Sources
PP5 No reputable source (clinical diagnostic laboratory, expert panel, or published literature) has reported this variant as pathogenic. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no clinical laboratory or publication asserting pathogenicity for this variant
Still missing
- No clinical or literature assertion of pathogenicity
Sources
BA1 Allele frequency is 0.0 across gnomAD v2.1, v4.1, and gnomAD-Canada, far below the BA1 threshold of >1%. Details ▾Hide ▴
BS1 Allele frequency is 0.0, well below the >0.3% threshold for BS1. This variant is not observed at a frequency greater than expected for the associated disorder. Details ▾Hide ▴
Evidence considered
- gnomAD AF=0 across all populations
- does not exceed BS1 threshold
Sources
BS2 No data on observation of this variant in healthy adult controls. The variant is absent from all population databases, precluding any assessment of healthy carrier status. Details ▾Hide ▴
Evidence considered
- Variant absent from gnomAD
- no healthy adult carrier data available
Still missing
- No control population data with confirmed healthy adult carriers
Sources
BS3 No functional studies evaluating p.Trp566Leu were identified. No evidence exists to demonstrate that this variant has no damaging effect on FBXW7 protein function. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional studies available
Still missing
- No functional assay data for this variant
Sources
BS4 No cosegregation data are available. Absence of segregation with disease cannot be demonstrated without family studies. Details ▾Hide ▴
Evidence considered
- No family or pedigree data available
Still missing
- No segregation analysis data
BP1 BP1 applies to missense variants in genes where only truncating variants cause disease. FBXW7 germline disease includes both missense and loss-of-function variants, with pathogenic missense variants reported in the WD40 domain (including codon 566). Therefore BP1 is not applicable. Details ▾Hide ▴
Evidence considered
- FBXW7 disease mechanism includes both missense and LoF variants
- germline missense variants in the WD40 domain are established as pathogenic
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a known pathogenic FBXW7 variant. No phase data are available. Details ▾Hide ▴
Evidence considered
- No trans phase data available
Still missing
- No observations in trans with pathogenic variants
BP4 Computational evidence does not support a benign effect. REVEL predicts a damaging score of 0.863, and BayesDel (0.424) does not strongly indicate a benign outcome. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL=0.863 (damaging
- inconsistent with BP4)
- BayesDel=0.424 (borderline)
- SpliceAI=0.12 (no splice impact)
Sources
BP5 No case was identified where this variant was found in an individual with an alternate molecular basis for disease. No patient-level data are available. Details ▾Hide ▴
Evidence considered
- No cases with alternate molecular etiology documented
Still missing
- No patient data with alternate molecular diagnosis
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no clinical laboratory or publication asserting benign classification
Still missing
- No clinical or literature assertion of benignity
Sources
PS5 No established pathogenic variant at the same codon (Trp566) with a different amino acid change was identified in ClinVar or the literature. PM5 candidate search yielded no same-residue comparator variants. Details ▾Hide ▴
Evidence considered
- No pathogenic comparator variant at p.Trp566 with a different amino acid substitution found in ClinVar
Still missing
- No alternative missense at codon 566 documented as pathogenic
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_033632.3:c.1697G>T is a missense variant (p.Trp566Leu) in FBXW7 exon 11. It does not fall into any of the default generic PVS1 null-variant buckets (nonsense, frameshift, canonical ±1,2 splice consensus). Per ClinGen SVI PVS1 recommendations (PMC6185798), PVS1 is not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- variant_bucket='other'
- apply_generic_pvs1_framework=false
Sources
PM3 N/APM3 applies to recessive disorders where a variant is observed in trans with a pathogenic variant. No FBXW7 germline disease is established as recessive, and no trans data are available. Details ▾Hide ▴
Evidence considered
- FBXW7 germline disease follows dominant/heterozygous inheritance pattern
- no recessive model or trans observations
PM4 N/APM4 applies to non-frameshift deletion/insertion variants or stop-loss variants. NM_033632.3:c.1697G>T is a missense substitution, not an in-frame indel or stop-loss. Details ▾Hide ▴
Evidence considered
- Missense substitution
- PM4 is restricted to protein-length-altering variants (in-frame indels
- stop-loss)
PM5 N/ANo same-residue comparator variants meeting classic PM5 semantics were identified. PM5 candidate harvesting was skipped because eligible comparators could not be confirmed. Details ▾Hide ▴
Evidence considered
- No pathogenic missense variants at codon 566 with a different amino acid change identified in ClinVar
Sources
BP3 N/ABP3 applies to in-frame deletions/insertions in a repetitive region. NM_033632.3:c.1697G>T is a single-nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
Evidence considered
- Substitution variant
- not an in-frame indel
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_033632.3:c.1697G>T is a missense variant (p.Trp566Leu), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense variant p.Trp566Leu
- BP7 is restricted to synonymous variants
Identifiers
- Gene
- FBXW7
- Transcript
- NM_033632.3
- Coding (HGVS c.)
- NM_033632.3:c.1697G>T
- Protein (HGVS p.)
- NP_361014.1:p.(Trp566Leu)
- GRCh38
- chr4:152324342 C>A
- GRCh37
- chr4:153245494 C>A
- COSMIC
- COSV99662097
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in FBXW7
—
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 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
Other predictors
- REVEL
- 0.863
- BayesDel
- 0.424
How the predictions were used
PP3 In silico predictions provide only partial support for a deleterious effect. REVEL predicts a damaging score of 0.863 (above the 0.5 threshold), but BayesDel yields a score of 0.424 (below typical damaging thresholds). SpliceAI predicts no significant splice impact (max delta = 0.12). Without at least two concordant in silico predictors supporting pathogenicity, PP3 is not met under generic ACMG/AMP. Details ▾Hide ▴
Evidence considered
- REVEL=0.863 (damaging)
- BayesDel=0.424 (borderline/not damaging)
- SpliceAI max delta=0.12 (no splice impact)
Still missing
- Discordant in silico predictions
- REVEL damaging but BayesDel does not corroborate
Sources
BP4 Computational evidence does not support a benign effect. REVEL predicts a damaging score of 0.863, and BayesDel (0.424) does not strongly indicate a benign outcome. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL=0.863 (damaging
- inconsistent with BP4)
- BayesDel=0.424 (borderline)
- SpliceAI=0.12 (no splice impact)
Sources
BP7 N/ABP7 applies to synonymous (silent) variants with no predicted splice impact. NM_033632.3:c.1697G>T is a missense variant (p.Trp566Leu), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense variant p.Trp566Leu
- BP7 is restricted to synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.12). REVEL score = 0.863. BayesDel score = 0.424003.
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 0.120
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.1697G%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-153245494-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-152324342-C-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-152324342-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_033632.3%3Ac.1697…
- OncoKB ↗www.oncokb.org/gene/FBXW7/W566L
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=210735388
- 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
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 = 0.12). REVEL score = 0.863. BayesDel score = 0.424003.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FBXW7, a tumor suppressor involved in protein degradation, is inactivated by mutation in various cancer types, most frequently in endometrial and colo
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99662097, n = 2 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.