NM_033632.3:c.1922C>G

FBXW7 · NP_361014.1:p.(Ser641Ter) · NM_033632.3

GRCh37: chr4:153244235 G>C · GRCh38: chr4:152323083 G>C

Gene: FBXW7 Transcript: NM_033632.3

Final call

Likely Pathogenic

PVS1 moderate PM1 moderate PM2 moderate PP3 supporting

Variant details

Gene

FBXW7

Transcript

NM_033632.3

Protein

NP_361014.1:p.(Ser641Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules support a Likely Pathogenic classification based on the observed combination of pathogenic criteria.

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	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	PS1 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.
PS2	Not assessed	No de novo data with confirmed maternity and paternity are available for this variant in the reviewed literature or databases.
PS3	Not met	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.
PS4	Not assessed	No case-control studies or clinical cohort data reporting the prevalence of this variant in affected individuals versus controls were identified.
PS5	Not assessed	No ClinVar assertion from a reputable source is available for this variant. The variant is absent from ClinVar.	clinvar
PM1	Met	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.	PMID:18094723
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	PM5 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.	pm5_candidates
PM6	Not assessed	No de novo observation (maternity and paternity unconfirmed) has been reported for this variant in the literature or databases reviewed.
PP1	Not assessed	No segregation data are available for this variant in the reviewed literature or databases.
PP2	N/A	PP2 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.
PP3	Met	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 spliceai
PP4	Not assessed	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.
PP5	Not assessed	No ClinVar entry exists for this variant, and no reputable source has classified it. PP5 cannot be applied without a credible source asserting pathogenicity.	clinvar
BA1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	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	Not met	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.
BS4	Not assessed	No segregation data are available to evaluate non-segregation with disease.
BP1	N/A	BP1 applies to missense variants in genes where truncating variants are the predominant disease mechanism. This variant is a nonsense change, not a missense substitution.
BP2	Not assessed	No data on co-occurrence with a pathogenic variant in trans for a fully penetrant dominant gene are available.
BP4	Not met	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.	spliceai bayesdel
BP5	Not assessed	No observation in a case with an alternative molecular basis for disease is reported for this variant.
BP6	Not assessed	No ClinVar entry from a reputable source classifies this variant as benign.	clinvar
BP7	N/A	BP7 applies to synonymous variants with no predicted splice impact. This variant is a nonsense change, not a synonymous substitution.
BP3	N/A	BP3 applies to in-frame indels in repetitive regions without a known function. This variant is a substitution.
PM3	N/A	PM3 applies to recessive disorders with a pathogenic variant in trans. FBXW7-related disorders follow autosomal dominant inheritance with loss-of-function mechanism.
PM4	N/A	PM4 applies to in-frame deletions/insertions or stop-loss variants. This variant is a substitution producing a premature stop codon.

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.