Variant classification summary

NM_001349798.2:c.1393C>T

FBXW7 · NP_001336727.1:p.(Arg465Cys) · NM_001349798.2

GRCh37: chr4:153249385 G>A · GRCh38: chr4:152328233 G>A

Gene: FBXW7 Transcript: NM_001349798.2

Final call

Likely Pathogenic

PS3 strong PM1 moderate PM2 supporting

Variant details

Gene

FBXW7

Transcript

NM_001349798.2

Protein

NP_001336727.1:p.(Arg465Cys)

gnomAD AF

1.2558159978399964e-06 (v4.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic evidence: PS3 strong shows impaired FBXW7 substrate binding or degradation for R465C across multiple assays.

2

Pathogenic evidence: PM1 moderate places Arg465 in a recurrent WD40 substrate-binding hotspot.

3

Pathogenic evidence: PM2 supporting shows extremely low gnomAD frequency with no homozygotes.

Final determination: Under the generic ACMG/AMP 2015 fallback, one Strong pathogenic criterion plus one or two Moderate pathogenic criteria supports Likely Pathogenic; PM2 supporting is additional evidence and no benign rule is satisfied.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: reviewed reports describe c.1393C>T p.Arg465Cys itself, with no established alternate nucleotide change producing the same amino-acid substitution.	PMID:17909001 PMID:17646408 PMID:23095493 PMID:28963353
PS2	Not assessed	Not assessed: no proband-level de novo observation or confirmed maternity and paternity data are available.
PS3	Met	Met, strong: R465C repeatedly lost substrate binding or degradation activity across NOTCH1, cyclin E1, Aurora B, and KLF5 assays versus wild-type FBXW7.	PMID:17646408 PMID:17909001 PMID:23095493 PMID:28963353
PS4	Not assessed	Not assessed: tumor reports lack variant-specific affected-versus-control counts, so no odds ratio or 95% confidence interval can be compared with the >5.0 and excludes-1.0 thresholds.	PMID:17909001 PMID:17646408 gnomad_v4
PM1	Met	Met at moderate strength: Arg465 is a statistically significant recurrent hotspot in the WD40 substrate-binding region, while the observed allele frequency is 1.25582e-06.	hotspots PMID:17909001 PMID:28963353 PMID:17646408 PMID:23095493 gnomad_v4
PM2	Met	Met at supporting: gnomAD AF is 4.32e-6 in v2.1 and 1.26e-6 in v4.1, both below the <=0.0001 PM2 threshold, with zero homozygotes.	gnomad_v2 gnomad_v4
PM3	Not assessed	Not assessed: no case-specific pathogenic second allele or parent/offspring phase testing establishes this variant in trans.
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: R465H is a recurrent, functionally damaging comparator, but its pathogenic classification is not established in the available evidence.	PMID:28963353 PMID:17909001
PM6	Not assessed	Not assessed: no proband-level observation supports an assumed de novo variant without parental confirmation.
PP1	Not assessed	Not assessed: no affected relatives or informative family meioses are available to evaluate cosegregation.
PP2	Not assessed	Not assessed: the evidence does not establish both a low benign-missense rate and a common germline missense disease mechanism for FBXW7.
PP3	Not met	Not met: missense REVEL 0.593 is below the PP3 supporting threshold of 0.644, and the SpliceAI score is outside this criterion's applicable path.	revel
PP4	Not assessed	Not assessed: no patient phenotype or family history is provided to determine whether it is highly specific for a single-gene disease.
PP5	Not met	Not met: ClinVar shows one non-expert laboratory Pathogenic submission, not an exact-variant expert-panel classification required for PP5.	clinvar
BA1	Not assessed	Not assessed: gnomAD v2.1 and v4.1 lack grpmax FAF, so total AF values of 4.32e-6 and 1.26e-6 cannot establish the required 5% BA1 threshold.	gnomad_v2 gnomad_v4 clinvar
BS1	Not assessed	Not assessed: grpmax FAF and disorder-specific prevalence/penetrance inputs are unavailable, although observed total AF is only 4.32e-6 in v2.1 and 1.26e-6 in v4.1.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: gnomAD reports zero homozygotes, but no individual-level evidence shows a healthy adult carrier with the relevant inheritance state and expected full penetrance.	gnomad_v2 gnomad_v4
BS3	Not met	Not met: every exact-variant assay showed impaired FBXW7 substrate binding or degradation rather than preserved protein function versus wild-type controls.	PMID:17646408 PMID:17909001 PMID:23095493 PMID:28963353
BS4	Not assessed	Not assessed: no affected relatives with reliable genotypes are available to demonstrate lack of segregation.
BP1	Not assessed	Not assessed: loss-of-function disease evidence exists, but the available data do not show that FBXW7 disease is caused primarily by truncating variants.
BP2	Not assessed	Not assessed: no documented cis or trans phase observation with a pathogenic variant is available for this case.
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL 0.593 exceeds the BP4 supporting threshold of 0.29, and the SpliceAI score cannot substitute on this predictor path.	revel
BP5	Not assessed	Not assessed: no clinical case evidence shows an alternate molecular basis for the disease being evaluated.
BP6	Not met	Not met: ClinVar has no exact-variant expert-panel Benign or Likely benign classification and instead records one non-expert Pathogenic submission.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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