Variant classification summary

NM_033632.3:c.1436G>A

FBXW7 · NP_361014.1:p.(Arg479Gln) · NM_033632.3

GRCh37: chr4:153247366 C>T · GRCh38: chr4:152326214 C>T

Gene: FBXW7 Transcript: NM_033632.3

Final call

Likely Pathogenic

PS3 moderate PM1 moderate PM2 supporting PP2 supporting

Variant details

Gene

FBXW7

Transcript

NM_033632.3

Protein

NP_361014.1:p.(Arg479Gln)

gnomAD AF

6.200689020563965e-07 (v4.1)

ClinVar

Tier I - Strong

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PS3 (Moderate): a functional rescue assay showed the R479Q allele impairs FBXW7 substrate degradation (p=0.035).

2

PM1 (Moderate): p.Arg479Gln lies in the FBXW7 WD40 substrate-recognition domain at a statistically significant recurrent mutation hotspot.

3

PM2 (Supporting): the variant is essentially absent from population databases, with one gnomAD v4.1 allele and no homozygotes.

4

PP2 (Supporting): missense substitution, not truncation, is the established dominant-negative FBXW7 oncogenic mechanism.

5

Overall: 2 Moderate + 2 Supporting under generic ACMG/AMP 2015 rules -> Likely Pathogenic.

Final determination: Generic ACMG/AMP 2015 fallback rule: 2 Moderate + 2 Supporting combine to Likely Pathogenic.

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	Not applicable: this missense substitution is not a null-variant class, so no nonsense-mediated decay or truncation mechanism is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no alternate nucleotide change producing the same p.Arg479Gln substitution with established pathogenicity was identified.
PS2	Not assessed	Not assessed: no proband or parental genotype data were available to establish a confirmed de novo occurrence.
PS3	Met	Met (Moderate): rescue with wild-type FBXW7 significantly lowered TGIF1 substrate levels in the R479Q cell line (p=0.035), demonstrating impaired degradation function. Strength is capped at Moderate because the evidence comes from a single, non-replicated study.	PMID:23676439
PS4	Not assessed	Not assessed: no affected-versus-control counts or statistical enrichment analysis was available for this variant.
PM1	Met	Met (Moderate): p.Arg479Gln lies in the FBXW7 WD40 substrate-recognition domain at a statistically significant recurrent mutation hotspot.	PMID:23676439
PM2	Met	Met (Supporting): essentially absent from population databases, with a single gnomAD v4.1 allele (AF 6.2e-07) and no homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no second pathogenic allele or trans-phase genotype was available to evaluate recessive inheritance.	final_classification_framework pvs1_gene_context
PM4	N/A	Not applicable: the missense substitution causes no protein length change, so this in-frame indel and stop-loss criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different missense change at residue 479 with an independent pathogenic classification was identified.
PM6	Not assessed	Not assessed: no documented de novo occurrence or parental testing result was available.
PP1	Not assessed	Not assessed: no pedigree or relative genotype data were available to evaluate segregation with disease.
PP2	Met	Met (Supporting): missense substitution, not truncation, is the documented predominant FBXW7 oncogenic mechanism, acting dominant-negatively at propeller-tip arginines.	PMID:23676439
PP3	Not met	Not met: REVEL 0.479 is below the >=0.7 PP3 threshold, and SpliceAI max delta 0.044 indicates no splice impact.	spliceai revel bayesdel
PP4	Not assessed	Not assessed: no patient phenotype or clinical findings were available for phenotype-to-gene comparison.
PP5	Not met	Not met: ClinVar entry 4530535 has no expert-panel pathogenic classification, only single-submitter somatic assertions.	clinvar
BA1	Not met	Not met: the gnomAD allele frequency (6.2e-07) is far below the stand-alone benign frequency range for BA1.	gnomad_v4
BS1	Not met	Not met: the single observed allele is far too rare to exceed the frequency expected for an FBXW7-associated disorder.	gnomad_v4
BS2	Not met	Not met: no gnomAD homozygotes are reported, and the variant was not observed in a documented healthy adult.	gnomad_v4
BS3	Not met	Not met: no study reports normal FBXW7 function for R479Q; all available functional data show loss of substrate-degradation activity.
BS4	Not assessed	Not assessed: no informative non-segregation observation, such as an affected relative lacking the variant, was available.
BP1	Not met	Not met: missense, not truncation, is the established FBXW7 disease mechanism, so the truncation-biased premise does not hold.	PMID:23676439
BP2	Not assessed	Not assessed: no genotype showing this variant in cis or trans with a pathogenic FBXW7 variant was available.	final_classification_framework clinvar
BP3	N/A	Not applicable: the missense substitution does not alter protein length in a repetitive region, so this criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.479 is above the <0.29 benign cutoff, and SpliceAI max delta 0.044 alone cannot support a benign impact.	spliceai revel bayesdel
BP5	Not assessed	Not assessed: no alternative molecular diagnosis or phenotype attributable to another cause was documented.
BP6	Not met	Not met: ClinVar entry 4530535 has no expert-panel Benign or Likely benign classification.	clinvar
BP7	N/A	Not applicable: the variant is missense, not synonymous, so this silent-variant criterion does not apply.	generic_acmg_combination_rules

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.