FBXW7

Final classification

Likely Pathogenic

FBXW7 c.1922C>G · p.Ser641Ter

FBXW7

Gene

FBXW7

Transcript

NM_033632.3

HGVS · transcript:coding

NM_033632.3:c.1922C>G

Consequence

N/A

GRCh38

chr4:152323083 G>C

GRCh37

chr4:153244235 G>C

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 moderate, PM1 moderate, PM2 moderate, PP3 supporting; combination = 3 moderate + 1 supporting, which maps to Likely Pathogenic. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PVS1 moderate, PM1 moderate, PM2 moderate, PP3 supporting; combination = 3 moderate + 1 supporting, which maps to Likely Pathogenic.

Classification rationale

PVS1PM1PM2PP3 Likely Pathogenic

FBXW7 c.1922C>G

PVS1 (moderate): NM_033632.3:c.1922C>G is a nonsense variant (p.Ser641Ter) in the terminal exon that escapes nonsense-mediated decay but truncates the WD40 substrate-recognition domain, a critical functional region of FBXW7.¹ PM1 (moderate): The truncation at residue 641 removes C-terminal WD40 repeats within the beta-propeller substrate-recognition domain, a well-characterized critical functional domain of FBXW7.² PM2 (moderate): The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), supporting rarity as a pathogenic attribute.³ PP3 (supporting): BayesDel in silico prediction score of 0.655873 supports a pathogenic effect.⁴ Combined evidence: PVS1 (moderate) + PM1 (moderate) + PM2 (moderate) + PP3 (supporting) = 3 moderate and 1 supporting criterion. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), 3 moderate criteria satisfy the Likely Pathogenic threshold.⁵

PVS1 + PM1 + PM2 + PP3 → Likely Pathogenic

1 pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

2 PMID:18094723 ↗

3 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

4 bayesdel

5 generic_acmg_combination_rules

Gene diagram · NM_033632.3 · variants mapped to exon structure

FBXW7 NM_033632.3

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 16 assessed

Applied · 4

Strength Supporting Moderate Strong Very strong

✓

PVS1 moderate Pathogenic

NM_033632.3:c.1922C>G is a nonsense variant (p.Ser641Ter) in the terminal exon (exon 12/12, c.1856 to *1623). The premature termination codon at position 641 escapes nonsense-mediated decay because it lies in the last exon with no downstream exon-exon junction. Under ClinGen SVI PVS1 guidelines (PMC6185798), nonsense variants in the terminal exon that escape NMD are downgraded from full-strength PVS1. However, the truncation removes the C-terminal 67 amino acids (residues 642-708) that include portions of the WD40 repeat beta-propeller domain, the substrate-recognition module essential to FBXW7 E3 ubiquitin ligase function. The truncation is therefore expected to impair substrate binding. PVS1 is applied at moderate strength reflecting the balance of terminal exon location (no NMD) against the critical functional domain affected.

Nonsense variant p.Ser641Ter in terminal exon (exon 12/12) of FBXW7Premature termination codon escapes NMD (no downstream exon-exon junction)Truncation removes 67 C-terminal residues including portions of WD40 substrate-recognition domain

pvs1_generic_framework ↗

✓

PM1 moderate Pathogenic

The variant p.Ser641Ter truncates the C-terminal portion of the WD40 repeat beta-propeller domain, the substrate-recognition module of FBXW7 that is structurally and functionally characterized in the literature. The WD40 repeats form an eight-bladed beta-propeller that directly binds phosphorylated substrates including cyclin E, MYC, JUN, and NOTCH1. Truncation at residue 641 removes the terminal WD40 repeats, which are essential structural components of the binding barrel. This satisfies PM1 at domain level for a variant in a well-characterized critical functional domain.

WD40 repeat domain is the substrate-recognition module of FBXW7forming an eight-bladed beta-propeller (PMID:18094723)Germline FBXW7 variants cluster in the WD40 domain and disrupt substrate recognition (PMID:35395208

PMID:18094723 ↗

✓

PM2 moderate Pathogenic

The variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Under non-VCEP gnomAD thresholds, an allele frequency below 0.1% in all populations satisfies PM2 at moderate strength for a rarity-based criterion.

Absent from gnomAD v2.1Absent from gnomAD v4.1Absent from gnomAD-Canada v1.0

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP3 supporting Pathogenic

BayesDel predicts a pathogenic score of 0.655873 for this variant. While SpliceAI predicts no splicing impact (max delta score 0.00), the BayesDel score passes the high-confidence pathogenic threshold, providing supporting in silico evidence. REVEL and HCI prior scores are not available. The combined in silico evidence is weighted by BayesDel, which is calibrated for both missense and nonsense predictions.

BayesDel score: 0.655873 (pathogenic-leaning)SpliceAI max delta score: 0.00 (no predicted splice impact)REVEL: not available

spliceai ↗

Assessed · not applied

Pathogenic

PS2 No de novo data with confirmed maternity and paternity are available for this variant in the reviewed literature or databases.

PS3 No variant-specific functional data were identified.

PS4 No case-control studies or clinical cohort data reporting the prevalence of this variant in affected individuals versus controls were identified.

PM6 No de novo observation (maternity and paternity unconfirmed) has been reported for this variant in the literature or databases reviewed.

PP1 No segregation data are available for this variant in the reviewed literature or databases.

PP4 No individual clinical phenotype data are available for this variant.

PP5 No ClinVar entry exists for this variant, and no reputable source has classified it.

Benign

BA1 The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), with an allele frequency of 0.

BS1 The variant is absent from all population databases, with an allele frequency of 0.

BS2 No data are available regarding the observation of this variant in healthy adults at an age where the FBXW7-related phenotype would have been fully penetrant.

BS3 No well-established functional studies demonstrate a neutral effect for this variant.

BS4 No segregation data are available to evaluate non-segregation with disease.

BP2 No data on co-occurrence with a pathogenic variant in trans for a fully penetrant dominant gene are available.

BP4 Multiple lines of in silico evidence do not support a benign interpretation.

BP5 No observation in a case with an alternative molecular basis for disease is reported for this variant.

BP6 No ClinVar entry from a reputable source classifies this variant as benign.

N/A · 8 PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7

Research & evidence

Population frequency · supports pathogenic

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

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.655873.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

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; COSV55906561, n = 3 times).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 2 further PMIDs triaged but not cited — see Sources & References.

FBW7 ubiquitin ligase: a tumour suppressor at the crossroads of cell division, growth and differentiation.

PMID 18094723 ↗ ONCOKB · functional

Searched

c.1922C>Gp.Ser641TerS641*Ser641Ter1922

Found

Comprehensive review of FBW7 ubiquitin ligase structure and function. Describes the WD40 repeat beta-propeller domain as the substrate-recognition module and catalogues cancer-associated FBW7 mutations. NM_033632.3:c.1922C>G (p.Ser641Ter) is not specifically mentioned, but the review establishes that the WD40 domain is a critical functional region and that mutations disrupting it cause loss of substrate degradation.

Variant

◇ Residue / gene-level — variant not named

Applied to

→PM1 supports · met

Why

Variant not specifically mentioned; cited for PM1 domain-level evidence that the WD40 repeats form the critical substrate-recognition domain of FBXW7.

FBW7 also contains a stretch of eight WD40 repeats that make multiple contacts with the substrate. WD40 repeats are protein interaction domains, and in the case of FBW7 (and Cdc4) crystallographic studies have shown that the WD40 repeats form an eight-bladed barrel-shaped β-propeller structure with defined phospho-degron binding pockets.

Location Throughout; domain architecture described in Figure 2 and associated text; WD40 repeat function detailed in body · full text

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 2 PMIDs not cited in assessment

15103331 ↗ Phosphorylation-dependent degradation of c-Myc is mediated by the F-box protein Fbw7. ONCOKB

17646409 ↗ FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. ONCOKB