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).1 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.2 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 PP3.3 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.4
FBXW7
Final classification
VUS
FBXW7 c.1697G>T · p.Trp566Leu
FBXW7
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).
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.
Classification rationale
PM2
VUS
FBXW7 c.1697G>T
PM2
→
VUS
2
pvs1_gene_context
3
revelbayesdelspliceai ↗
Gene diagram
· NM_033632.3 · variants mapped to exon structure
FBXW7
NM_033632.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
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%.
Absent from gnomAD v2.1 (AC=0)Absent from gnomAD v4.1 (AC=0)Absent from gnomAD-Canada v1.0 (AC=0)
Assessed · not applied
Pathogenic
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.
PS2
No de novo occurrence data are available for this variant.
PS3
No well-established functional studies evaluating the specific impact of p.Trp566Leu on FBXW7 protein function were identified.
PS4
No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals compared to controls.
PM1
p.Trp566Leu lies within the WD40 repeat domain of FBXW7, a region critical for substrate recognition and frequently mutated in disease.
PM6
No de novo occurrence data are available for this variant.
PP1
No cosegregation data are available for this variant.
PP2
Insufficient data to establish that FBXW7 has a low rate of benign missense variation as required for PP2.
PP3
In silico predictions provide only partial support for a deleterious effect.
PP4
No proband phenotype or clinical data are available for this variant.
PP5
No reputable source (clinical diagnostic laboratory, expert panel, or published literature) has reported this variant as pathogenic.
Benign
BA1
Allele frequency is 0.0 across gnomAD v2.1, v4.1, and gnomAD-Canada, far below the BA1 threshold of >1%.
BS1
Allele frequency is 0.0, well below the >0.3% threshold for BS1.
BS2
No data on observation of this variant in healthy adult controls.
BS3
No functional studies evaluating p.Trp566Leu were identified.
BS4
No cosegregation data are available.
BP1
BP1 applies to missense variants in genes where only truncating variants cause disease.
BP2
No observation of this variant in trans with a known pathogenic FBXW7 variant.
BP4
Computational evidence does not support a benign effect.
BP5
No case was identified where this variant was found in an individual with an alternate molecular basis for disease.
BP6
No reputable source has reported this variant as benign.
N/A · 6
PVS1 · PM3 · PM4 · PM5 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
Absent from gnomAD v4.1.
v2.1
Absent from gnomAD v2.1.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
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
Unknown Oncogenic Effect
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
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV99662097, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links