NM_033632.3:c.1697G>T

FBXW7 · NP_361014.1:p.(Trp566Leu) · NM_033632.3

GRCh37: chr4:153245494 C>A · GRCh38: chr4:152324342 C>A

Gene: FBXW7 Transcript: NM_033632.3

Final call

VUS

PM2 supporting

Variant details

Gene

FBXW7

Transcript

NM_033632.3

Protein

NP_361014.1:p.(Trp566Leu)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_generic_framework
PS1	Not met	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.	clinvar
PS2	Not met	No de novo occurrence data are available for this variant. No proband or trio sequencing data were identified in ClinVar or the literature.	clinvar
PS3	Not met	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.	oncokb
PS4	Not met	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.	clinvar gnomad_v2 gnomad_v4
PS5	Not met	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.	clinvar
PM1	Not met	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.
PM2	Met	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%.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator variants meeting classic PM5 semantics were identified. PM5 candidate harvesting was skipped because eligible comparators could not be confirmed.	clinvar
PM6	Not met	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.	clinvar
PP1	Not met	No cosegregation data are available for this variant. No family studies or pedigree analyses were identified.
PP2	Not met	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not met	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.	clinvar
PP5	Not met	No reputable source (clinical diagnostic laboratory, expert panel, or published literature) has reported this variant as pathogenic. The variant is absent from ClinVar entirely.	clinvar
BA1	Not met	Allele frequency is 0.0 across gnomAD v2.1, v4.1, and gnomAD-Canada, far below the BA1 threshold of >1%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	No functional studies evaluating p.Trp566Leu were identified. No evidence exists to demonstrate that this variant has no damaging effect on FBXW7 protein function.	oncokb
BS4	Not met	No cosegregation data are available. Absence of segregation with disease cannot be demonstrated without family studies.
BP1	Not met	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.	pvs1_gene_context
BP2	Not met	No observation of this variant in trans with a known pathogenic FBXW7 variant. No phase data are available.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not met	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.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar entirely.	clinvar
BP7	N/A	BP7 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.
BP3	N/A	BP3 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.
PM3	N/A	PM3 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.
PM4	N/A	PM4 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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.