FBXW7c.1922C>GLikely pathogenic

Print report

Variant interpretation report

FBXW7 c.1922C>G, p.(Ser641Ter)

NM_033632.3:c.1922C>G NP_361014.1:p.(Ser641Ter) View identifiers

Classification

Likely pathogenic

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.

Likely pathogenic.A likely pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About FBXW7

No gene-level summary was recorded for this case.

Key facts

Evidence used: 3 moderate (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 14 Jul 2026 · version 7.0.3

Evidence considered

View criteria

Applied evidence criteria

PVS1 (moderate): 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.
PM1 (moderate): 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.
PM2 (moderate): 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.
PP3 (supporting): 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.

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: 4 Benign evidence criteria: 0

Pathogenic criteria applied · 4

PVS1Moderate

PVS1 · moderate

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.

PM1Moderate

PM1 · moderate

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.

PM2Moderate

PM2 · moderate

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.

PP3Supporting

PP3 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: 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.

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.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.000 maximum delta

Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

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

No listed criterion applied OncoKB ↗

COSMIC

Cancer Hotspots

Somatic evidence

3 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55906561, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 4 met · 5 not met · 12 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM3 PM4 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP3 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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.

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.

PM2 (moderate): The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), supporting rarity as a pathogenic attribute.

PP3 (supporting): BayesDel in silico prediction score of 0.655873 supports a pathogenic effect.

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.

Met · 4

PVS1 ModerateNM_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. Details ▾Hide ▴

Evidence considered

Nonsense variant p.Ser641Ter in terminal exon (exon 12/12) of FBXW7
Premature termination codon escapes NMD (no downstream exon-exon junction)
Truncation removes 67 C-terminal residues including portions of WD40 substrate-recognition domain
FBXW7 loss-of-function is an established germline disease mechanism (FBXW7-related neurodevelopmental syndrome
Wilms tumor predisposition)

Still missing

Exact impact of C-terminal truncation on β-propeller structure has not been experimentally characterized for this specific variant

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PM1 ModerateThe 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. Details ▾Hide ▴

Evidence considered

WD40 repeat domain is the substrate-recognition module of FBXW7
forming an eight-bladed beta-propeller (PMID:18094723)
Germline FBXW7 variants cluster in the WD40 domain and disrupt substrate recognition (PMID:35395208
PMID:42111496)
Truncation at S641 removes the terminal WD40 repeats
predicted to disrupt beta-propeller structure and substrate binding

Sources

PMID:18094723 ↗

PM2 ModerateThe 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. Details ▾Hide ▴

Evidence considered

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

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

PP3 SupportingBayesDel 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. Details ▾Hide ▴

Evidence considered

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

Still missing

REVEL score unavailable for independent confirmation of in silico prediction

Sources

bayesdelspliceai ↗

Not met · 5 · evaluated, threshold not reached

PS3 No variant-specific functional data were identified. Three publications (PMID:15103331, PMID:17646409, PMID:18094723) were reviewed; none report experimental characterization of NM_033632.3:c.1922C>G (p.Ser641Ter). The publications describe FBXW7 ubiquitin ligase function at the gene and domain level, but do not constitute variant-specific experimental evidence meeting PS3 standards. Details ▾Hide ▴

Evidence considered

No functional studies tested the exact variant or a systematically characterized range that includes position S641

Still missing

Functional characterization of p.Ser641Ter (e.g.
ubiquitination assay
substrate degradation assay) would be needed to apply PS3

BA1 The variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), with an allele frequency of 0. The BA1 threshold of >1% allele frequency is not met. Details ▾Hide ▴

Evidence considered

Allele frequency is 0 across all population databases
well below the BA1 threshold of >1%

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 The variant is absent from all population databases, with an allele frequency of 0. The BS1 threshold of >0.3% allele frequency is not met. Details ▾Hide ▴

Evidence considered

Allele frequency is 0 across all population databases
well below the BS1 threshold of >0.3%

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS3 No well-established functional studies demonstrate a neutral effect for this variant. The reviewed literature describes FBXW7 loss-of-function as pathogenic; no evidence supports a benign functional effect for p.Ser641Ter. Details ▾Hide ▴

Evidence considered

No functional study demonstrates a benign or neutral effect for p.Ser641Ter

Still missing

Functional data showing no deleterious effect would be required to apply BS3

BP4 Multiple lines of in silico evidence do not support a benign interpretation. SpliceAI predicts no splice impact (max delta 0.00), but BayesDel score of 0.655873 is pathogenic-leaning. The in silico evidence considered in aggregate does not satisfy BP4, which requires multiple lines of computational evidence supporting no impact on the gene product. Details ▾Hide ▴

Evidence considered

SpliceAI: max delta 0.00 (no predicted splicing impact)
BayesDel: 0.655873 (pathogenic-leaning)
Mixed in silico evidence — does not meet BP4 threshold for benign computational consensus

Sources

spliceai ↗bayesdel

Not assessed · 12 · no assessment recorded

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

Still missing

De novo status cannot be evaluated without parental genotype data

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

Still missing

Case-control association data for FBXW7:c.1922C>G are not available

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

Still missing

No de novo reports available for this variant

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

Still missing

Family segregation data not available

PP4 No individual clinical phenotype data are available for this variant. The variant has been observed in 3 somatic cancer samples (COSMIC COSV55906561) but no germline clinical phenotype is reported. Details ▾Hide ▴

Evidence considered

COSMIC COSV55906561: 3 somatic observations
no germline phenotype data

Still missing

No germline clinical phenotype or patient data available

PP5 No ClinVar entry exists for this variant, and no reputable source has classified it. PP5 cannot be applied without a credible source asserting pathogenicity. Details ▾Hide ▴

Evidence considered

Variant is absent from ClinVar

Still missing

No ClinVar classification available

Sources

clinvar ↗

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. Details ▾Hide ▴

Still missing

Healthy adult carrier data not available

BS4 No segregation data are available to evaluate non-segregation with disease. Details ▾Hide ▴

Still missing

Segregation data not available

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

Still missing

No co-occurrence data available

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

Still missing

No data on alternative molecular basis in cases carrying this variant

BP6 No ClinVar entry from a reputable source classifies this variant as benign. Details ▾Hide ▴

Evidence considered

Variant is absent from ClinVar

Still missing

No ClinVar benign classification available

Sources

clinvar ↗

PS5 No ClinVar assertion from a reputable source is available for this variant. The variant is absent from ClinVar. Details ▾Hide ▴

Evidence considered

Variant is absent from ClinVar

Still missing

No ClinVar entry exists for this variant

Sources

clinvar ↗

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 applies to missense variants with a different amino acid change at the same residue that is known to be pathogenic. This variant is a nonsense change (p.Ser641Ter), not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM3 N/APM3 applies to recessive disorders with a pathogenic variant in trans. FBXW7-related disorders follow autosomal dominant inheritance with loss-of-function mechanism. Details ▾Hide ▴

No further detail was recorded.

PM4 N/APM4 applies to in-frame deletions/insertions or stop-loss variants. This variant is a substitution producing a premature stop codon. Details ▾Hide ▴

No further detail was recorded.

PM5 N/APM5 applies to missense variants at the same amino acid residue as a known pathogenic missense change. This variant is a nonsense change (p.Ser641Ter), not a missense substitution. No clinically classified missense comparators at S641 were identified. Details ▾Hide ▴

Sources

pm5_candidates

PP2 N/APP2 applies to missense variants in genes where missense is a common disease mechanism and benign missense variation is low. This variant is a nonsense change, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP1 N/ABP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. This variant is a nonsense change, not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ABP3 applies to in-frame indels in repetitive regions without a known function. This variant is a substitution. Details ▾Hide ▴

No further detail was recorded.

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense change, not a synonymous substitution. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: FBXW7
Transcript: NM_033632.3
Coding (HGVS c.): NM_033632.3:c.1922C>G
Protein (HGVS p.): NP_361014.1:p.(Ser641Ter)
GRCh38: chr4:152323083 G>C
GRCh37: chr4:153244235 G>C
COSMIC: COSV55906561

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

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Transcript span

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Strand

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Variants mapped

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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

SpliceAI acceptor lossat -135 bp

0.000

SpliceAI acceptor gainat +474 bp

0.000

SpliceAI donor lossat +187 bp

0.000

SpliceAI donor gainat +387 bp

0.000

Pangolin splice lossmagnitude shown

-0.060

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: 0.656

How the predictions were used

Evidence considered

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

Still missing

REVEL score unavailable for independent confirmation of in silico prediction

Sources

bayesdelspliceai ↗

Evidence considered

SpliceAI: max delta 0.00 (no predicted splicing impact)
BayesDel: 0.655873 (pathogenic-leaning)
Mixed in silico evidence — does not meet BP4 threshold for benign computational consensus

Sources

spliceai ↗bayesdel

BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense change, not a synonymous substitution. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

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

3 paper records listed. 1 cited in the classification. None of the listed paper records explicitly indicates that the variant is named.

Cited in the classification

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

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.
→ PM1 Does not name this variant
PMID 18094723 ↗
Source detail

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

Other recorded publications

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

Describes phosphorylation-dependent degradation of c-Myc by Fbw7. Demonstrates that Fbw7 interacts with c-Myc in a manner dependent on phosphorylation of threonine-58, a residue frequently mutated in cancer. NM_033632.3:c.1922C>G was not identified in this paper.
Does not name this variant
PMID 15103331 ↗
FBW7 mutations in leukemic cells mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors.

Characterizes FBW7 mutations in T-ALL cell lines that mediate NOTCH pathway activation and resistance to gamma-secretase inhibitors. Reports FBW7 mutations in the WD40 domain in leukemic cells but does not identify NM_033632.3:c.1922C>G.
Does not name this variant
PMID 17646409 ↗

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 0.000 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

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 = 0.00). BayesDel score = 0.655873.

Functional

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

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55906561, n = 3 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.