NM_033632.3:c.608C>T

FBXW7 · NP_361014.1:p.(Ser203Leu) · NM_033632.3

GRCh37: chr4:153268200 G>A · GRCh38: chr4:152347048 G>A

Gene: FBXW7 Transcript: NM_033632.3

Final call

VUS

PM2 moderate BP4 moderate

Variant details

Gene

FBXW7

Transcript

NM_033632.3

Protein

NP_361014.1:p.(Ser203Leu)

gnomAD AF

3.7436077896990887e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Moderate): extremely rare in population data — gnomAD v4.1 AF 3.74e-06 (6/1,602,732 alleles), with no homozygotes observed.

BP4 (Moderate): REVEL 0.076 is below the 0.183 benign-moderate threshold and SpliceAI max delta 0.012 predicts no splicing disruption, indicating a benign computational profile.

Final classification: Uncertain Significance — PM2 (Moderate) plus BP4 (Moderate) reaches no Benign or Pathogenic threshold under the generic ACMG/AMP 2015 combination rules.

Final determination: Generic ACMG/AMP 2015 fallback: with only PM2 (Moderate) and BP4 (Moderate) met, no Pathogenic/Likely Pathogenic/Benign/Likely Benign combination is satisfied, so the variant is classified as Uncertain Significance.

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 is a missense substitution, not a null variant, so no loss-of-function mechanism such as nonsense-mediated decay is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic variant producing the same p.Ser203Leu amino acid change was available.	clinvar
PS2	Not assessed	Not assessed: no proband phenotype or parental testing result was available to establish a de novo occurrence.	final_classification_framework generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no functional or experimental assay data for this variant was available.	oncokb
PS4	Not assessed	Not assessed: no case series or case-control enrichment data was available.
PM1	Not met	Not met: residue 203 lies outside the F-box and WD40 substrate-recognition domains, with only 2 somatic COSMIC occurrences and no significant hotspot.	pvs1_gene_context
PM2	Met	Met (Moderate): extremely rare in population data — gnomAD v4.1 AF 3.74e-06 (6/1,602,732 alleles), with no homozygotes observed.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no affected proband with a pathogenic FBXW7 variant in trans was available.	generic_acmg_combination_rules pvs1_gene_context
PM4	N/A	Not applicable: the missense change does not alter protein length, so the criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no established pathogenic variant at residue 203 (e.g., p.Ser203Pro) was identified.	pm5_candidates
PM6	Not assessed	Not assessed: no parental testing result was available to establish a presumed de novo occurrence.	final_classification_framework generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no family segregation or informative relatives data was available.	final_classification_framework generic_acmg_combination_rules
PP2	Not assessed	Not assessed: no quantitative missense constraint metric (e.g., gnomAD missense Z-score) was available.	pvs1_gene_context
PP3	Not met	Not met: REVEL 0.076 is below the 0.644 pathogenic-supporting threshold, and SpliceAI max delta 0.012 is far below 0.2.	revel spliceai
PP4	Not assessed	Not assessed: no proband phenotype or phenotype-to-FBXW7 specificity data was available.
PP5	Not met	Not met: the variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: the highest reliable allele frequency is 7.04e-05 (gnomAD v2.1 NFE), far below the stand-alone benign threshold.	gnomad_v2 gnomad_v4 generic_acmg_combination_rules
BS1	Not assessed	Not assessed: no FBXW7 disease-specific maximum credible allele frequency threshold was available.	gnomad_v2 gnomad_v4 final_classification_framework
BS2	Not assessed	Not assessed: no unaffected adult individuals with phenotype and age data incompatible with the condition were documented.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional assay data demonstrating normal protein function was available.	oncokb
BS4	Not assessed	Not assessed: no non-segregation observation was available.	final_classification_framework generic_acmg_combination_rules
BP1	Not met	Not met: missense variants are an established mechanism of FBXW7 germline disease, so a missense change is not inherently unlikely to be pathogenic.	pvs1_gene_context
BP2	Not assessed	Not assessed: no observation places the variant in cis or trans with a pathogenic FBXW7 variant.	generic_acmg_combination_rules pvs1_gene_context
BP3	N/A	Not applicable: the variant is a missense change, not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (Moderate): REVEL 0.076 is below the 0.183 benign-moderate threshold, and SpliceAI max delta 0.012 predicts no splicing disruption.	revel spliceai
BP5	Not assessed	Not assessed: no independent molecular diagnosis or phenotype data was available.
BP6	Not met	Not met: the variant is absent from ClinVar, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: the variant is missense, not a synonymous change, so the 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.