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 PP3 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, a gene in which germline loss-of-function variants cause a neurodevelopmental syndrome with Wilms tumor predisposition.

This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting the PM2 criterion at supporting strength.

In silico prediction with REVEL yields a score of 0.863, supporting a deleterious effect and meeting PP3 at supporting strength.

SpliceAI predicts no significant splicing impact (max delta score 0.12).

This variant has been reported in somatic cancers (COSMIC COSV99662097, n=2) but has not been observed in ClinVar or any germline disease cohort.

With only two supporting pathogenic criteria (PM2_Supporting, PP3_Supporting), this variant does not meet the threshold for Likely Pathogenic classification under generic ACMG/AMP 2015 combination rules.

This variant is classified as a Variant of Uncertain Significance (VUS).

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) that does not fall into any generic PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus variants) per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_generic_framework
PS1	Not assessed	No previously classified pathogenic missense variant at the same amino acid position (Trp566) was identified in ClinVar or literature; insufficient evidence to assess PS1.	clinvar
PS2	Not assessed	No de novo data (paternity and maternity confirmed) available for this variant; insufficient evidence to assess PS2.
PS3	Not assessed	No well-established functional studies demonstrating a deleterious effect specific to p.Trp566Leu were identified. OncoKB reports Unknown Oncogenic Effect; no variant-specific functional evidence found in literature.	oncokb
PS4	Not assessed	No case-control or cohort prevalence data available for this variant; insufficient evidence to assess PS4.
PS5	Not assessed	No alternative pathogenic variant at the same nucleotide position has been established; no comparator data available.
PM1	Not met	Residue Trp566 is not located in a statistically significant mutational hotspot per cancerhotspots.org. Without a VCEP-defined critical functional domain for FBXW7, PM1 cannot be applied at the residue level.
PM2	Met	This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0, meeting the non-VCEP PM2 threshold of <0.1% allele frequency.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No candidate comparator missense variants at residue Trp566 with a confirmed pathogenic classification were identified; automatic PM5 candidate harvesting was unable to find eligible comparators.	pm5_candidates
PM6	Not assessed	No de novo observation (with or without confirmed parentage) was identified for this variant; insufficient evidence to assess PM6.
PP1	Not assessed	No cosegregation data available for this variant; insufficient evidence to assess PP1.
PP2	Not assessed	No HCI prior probability or missense constraint (z-score) data available for FBXW7. While missense variants are a known germline disease mechanism in this gene, constraint metrics are needed to apply PP2.
PP3	Met	REVEL in silico predictor yields a score of 0.863, supporting a deleterious effect. SpliceAI shows no significant splice impact (max delta 0.12). BayesDel score of 0.424 is below the typical deleterious threshold, providing only one clear line of computational evidence.	revel spliceai bayesdel
PP4	Not assessed	No patient phenotype data specific to this variant is available; insufficient evidence to assess PP4.
PP5	Not assessed	No reputable source (ClinVar, expert panel, or published report) has classified this variant; insufficient evidence to assess PP5.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada; allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada; allele frequency does not exceed the non-VCEP BS1 threshold of >0.3%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on observation of this variant in healthy adults with full penetrance expected at an early age; insufficient evidence to assess BS2.
BS3	Not assessed	No well-established functional studies showing no deleterious effect for this variant are available; insufficient evidence to assess BS3.
BS4	Not assessed	No non-segregation data available for this variant; insufficient evidence to assess BS4.
BP1	Not met	Missense variants are a recognized mechanism of germline disease in FBXW7; pathogenic FBXW7 germline variants include missense, frameshift, and splice-site changes. BP1 is not applicable when missense variants are an established disease mechanism.	pvs1_gene_context
BP2	Not assessed	No observation of this variant in trans with a known pathogenic dominant variant; insufficient evidence to assess BP2.
BP3	N/A	BP3 applies to in-frame deletions/insertions in repetitive regions; this variant is a substitution.
BP4	Not met	REVEL score of 0.863 predicts a deleterious effect; computational evidence does not support a benign interpretation.	revel spliceai bayesdel
BP5	Not assessed	No observation of this variant in a case with an alternative molecular basis for disease; insufficient evidence to assess BP5.
BP6	Not assessed	No reputable source (ClinVar, expert panel) has classified this variant as benign; insufficient evidence to assess BP6.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact; this variant is a missense substitution (c.1697G>T, p.Trp566Leu).
PM3	N/A	PM3 applies to recessive disorders with a pathogenic variant in trans; FBXW7-associated disease follows autosomal dominant inheritance.
PM4	N/A	PM4 applies to protein length changes (in-frame deletions/insertions, stop-loss); this variant is a missense substitution.

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.