FBXW7 c.1436G>A, p.(Arg479Gln)

Reasoning

No VCEP/ClinGen expert-panel specification is available for FBXW7 (framework_mode = generic_acmg; cspec.found = false), so generic ACMG/AMP PS3 criteria were applied. PMID:23676439 (Davis et al.) provides variant-adjacent functional evidence: the SW1463 colorectal cancer cell line, which is heterozygous for the exact variant NM_033632.3 p.(Arg479Gln)/R479Q, was used in a WT-FBXW7 re-expression rescue assay. Re-expression of wild-type FBXW7 significantly reduced levels of the FBXW7 substrate TGIF1 in the R479Q-mutant SW1463 line (p=0.035, t test) and in the LOVO line carrying the analogous hotspot mutation R505C (p=0.006), whereas a control line carrying an unrelated truncating variant of uncertain significance (R278X) showed no significant TGIF1 decrease, indicating the assay has appropriate positive/negative comparator design. shRNA knockdown of FBXW7 in the R479Q/R505C-mutant lines produced no further increase in TGIF1, consistent with a strong pre-existing loss of substrate-degradation function attributable to the mutant allele. The same publication also reports an orthologous in vivo knock-in mouse model (Fbxw7 R482Q, equivalent to human R479Q) showing dominant-negative co-immunoprecipitation with wild-type Fbxw7, dosage-dependent accumulation of substrates (Klf5, Tgif1, cyclin E), and accelerated Apc-driven intestinal tumorigenesis compared with a null-allele model, biologically consistent with impaired substrate ubiquitination/degradation, the established mechanism of FBXW7 tumor suppression. This constitutes a biologically plausible, appropriately controlled functional readout directly implicating the variant residue in loss of FBXW7 substrate-degradation activity. Strength is capped at Moderate rather than Strong because the assay derives from a single publication (not independently replicated across separate research groups/laboratories), uses a somatic cancer cell line context (biallelic/complex genetic background) rather than an isogenic single-variant expression system, and no formalized clinical-grade functional assay validation (per ClinGen SVI PS3/BS3 recommendations) has been documented for this assay in a gene-specific framework.

Rule

PS3_moderate (generic ACMG/AMP 2015; no FBXW7 VCEP specification available)

Evidence considered

• PMID:23676439 (Davis et al., Gut 2013): SW1463 colorectal cancer cell line, heterozygous for R479Q, showed significant TGIF1 reduction upon wild-type FBXW7 re-expression (p=0.035, t test), while a truncating-variant control line (R278X) showed no significant TGIF1 change, indicating a variant-specific loss of substrate-degradation function rescued by WT protein.
• PMID:23676439: shRNA knockdown of FBXW7 in R479Q/R505C-mutant lines produced no further increase in TGIF1 (p=0.477), consistent with the mutant allele already conferring a strong loss-of-function/dominant-negative effect on substrate turnover.
• PMID:23676439: orthologous Fbxw7 R482Q knock-in mouse (equivalent to human R479Q) demonstrates dominant-negative co-immunoprecipitation with wild-type Fbxw7 protein, dosage-dependent elevation of substrates Klf5/Tgif1/cyclin E, and significantly accelerated Apc-mutant-driven intestinal tumorigenesis relative to a null Fbxw7 heterozygote, providing in vivo biological support for a damaging effect of the R479Q substitution on FBXW7 tumor-suppressor function via impaired substrate ubiquitination/degradation.

Still missing

• No independent replication of the R479Q-specific functional readout in a second publication or laboratory.
• Assay was performed in a cancer cell line with a complex background genotype rather than an isogenic single-variant expression system, limiting attribution specificity.
• No ClinGen SVI-style formal validation (sensitivity/specificity against known pathogenic/benign controls) of this TGIF1 rescue/knockdown assay has been documented, precluding assignment of Strong strength.

Sources

Reasoning

p.(Arg479Gln) falls within the FBXW7 WD40 beta-propeller substrate-recognition domain at a residue reported by cancerhotspots.org as a statistically significant recurrent mutation hotspot (query 'FBXW7 R479', search_status=result_found, found=true, evidence_sentence: 'This variant lies in a statistically significant hotspot'). Functional literature (PMID:23676439) independently corroborates that FBXW7 tumor-suppressor missense mutations recurrently and specifically target arginine residues at the beta-sheet propeller tips (naming R465, R479, R505, R658 as the recurrent propeller-tip residues) that mediate substrate recognition, and the identical R479Q change is used as a study allele (SW1463 cell line, heterozygous R479Q) alongside R505C as canonical propeller-tip mutations. This constitutes a well-characterized, functionally critical, mutation-dense subdomain, supporting PM1 at moderate strength per generic ACMG/AMP mutational hotspot/functional domain criteria (no FBXW7 VCEP-specific PM1 point system exists to override this).

Evidence considered

• cancerhotspots.org record 'FBXW7 R479': search_status=result_found, found=true, evidence_sentence='This variant lies in a statistically significant hotspot' (screenshot verification flagged as partial regex extraction, but hotspot designation itself is explicit).
• PMID:23676439 (full text): 'most mutations are monoallelic missense changes involving specific arginine residues at beta-sheet propellor tips that allow the FBXW7 protein to recognise its substrates' and 'colorectal cancer cell lines that carry propellor tip mutations (LOVO, heterozygous R505C and SW1463, heterozygous R479Q)' -- confirms R479 is one of the recurrently mutated propeller-tip substrate-recognition residues, the same functional subdomain/hotspot as this variant.
• OncoKB (evidence.json): biological_effect='Loss-of-function', classification='Oncogenic', is_variant_specific=true -- corroborates the propeller-tip region's functional criticality but was used only as supporting context, not as the primary PM1 basis.

Still missing

• No FBXW7-specific VCEP PM1 quantitative hotspot threshold/point system is available; assessment relies on cancerhotspots.org statistical-significance designation plus published structural/functional characterization of the propeller-tip mutation cluster rather than a codified VCEP rule.

Sources

Reasoning

The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0 and has only one allele in gnomAD v4.1 (total AF 6.200689e-07, with no homozygotes). This is sufficiently rare population evidence for PM2 at supporting strength.

Rule

Generic ACMG/AMP PM2 rarity criterion, applied at supporting strength in the absence of an FBXW7-specific specification.

Evidence considered

• gnomAD v2.1 reports the variant as absent.
• gnomAD-Canada v1.0 reports the variant as absent.
• gnomAD v4.1 reports total AC 1/AN 1,612,724 (AF 6.200689e-07), highest population AF 8.479520e-07 in non-Finnish Europeans, and zero homozygotes.

Still missing

• No FBXW7 disease-specific PM2 threshold or maximum credible allele-frequency calculation was available; the assessment therefore uses generic ACMG/AMP rarity evidence.

Sources

Reasoning

PP2 applies to missense variants in genes where missense change is a common disease/oncogenic mechanism and where benign missense variation is not common. Published functional characterization (PMID:23676439) explicitly states that FBXW7 has 'an unusual mutation spectrum whereby biallelic, simple loss-of-function mutations are rare; instead, most mutations are monoallelic missense changes involving specific arginine residues at beta-sheet propellor tips' acting in a dominant-negative fashion sufficient to drive tumorigenesis with only a single hit. This establishes missense substitution (rather than truncation) as the predominant, well-documented mechanism of FBXW7 pathogenicity/oncogenicity, consistent with the PP2 rationale; the recurrent propeller-tip missense hotspot cluster (including R479, R505, R465, R658) further supports that missense variation at these residues is disease-relevant and not simply tolerated background variation.

Evidence considered

• PMID:23676439: 'FBXW7 is classed as a tumour suppressor, but has an unusual mutation spectrum whereby biallelic, simple loss-of-function mutations are rare; instead, most mutations are monoallelic missense changes involving specific arginine residues at beta-sheet propellor tips that allow the FBXW7 protein to recognise its substrates... Propellor tip mutations most likely act as dominant negative, loss-of-function alleles that provide sufficient derangement for tumorigenesis' -- establishes missense change as the principal, well-established mechanism of FBXW7 pathogenicity rather than an incidental variant class.

Still missing

• No formal FBXW7 missense Z-score / missense constraint metric (e.g. gnomAD missense o/e or ExAC Z-score) was retrieved in this bundle to quantitatively confirm 'low rate of benign missense variation'; the mechanistic literature argument is used as the primary basis instead.

Sources

Reasoning

No gene-specific VCEP framework or CSPEC is available for FBXW7 in this case (cspec.found=false, final_classification_framework.source='generic_acmg_fallback'), so generic ACMG/AMP thresholds were used. NM_033632.3:c.1436G>A (p.Arg479Gln) is a missense variant. SpliceAI predicts no significant splice impact (max delta score = 0.044, well below the ~0.2 threshold used to flag possible splice disruption), so the splice-impact path does not support PP3. On the missense path, REVEL score is 0.479, which falls in the intermediate/indeterminate range and is below the ClinGen SVI-calibrated REVEL threshold (>=0.7 for PP3_Moderate, per PMID 36413997) required to apply PP3 at even the lowest calibrated strength. BayesDel score (0.0626477) is available but this pipeline has no verified published threshold/publication for BayesDel, so it is treated as not_available and cannot be used to support PP3. Overall, no calibrated computational predictor meets the threshold to apply PP3.

Evidence considered

• SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).' Scores: DS_AG=0.044, DS_AL=0.002, DS_DG=0.006, DS_DL=0.0; max_delta_score=0.044.
• REVEL score = 0.479 (local REVEL v1.3 lookup). ClinGen SVI calibrated REVEL threshold for PP3_Moderate is >=0.7 (PMID 36413997); 0.479 does not meet this threshold.
• BayesDel score = 0.0626477 (local BayesDel_170824_noAF lookup), but no verified published calibration threshold/publication is available to this pipeline for BayesDel, so it is treated as not_available for PP3 per pipeline policy.
• No CSPEC/VCEP framework found for FBXW7 (cspec.found=false); final_classification_framework.source='generic_acmg_fallback', so generic ACMG/AMP PP3/BP4 logic applies rather than a gene-specific lookup table.

Still missing

• No gene-specific (VCEP) PP3/BP4 lookup table available for FBXW7 to check for a pre-assigned code.
• BayesDel score exists but no verified published threshold/PMID is available to this pipeline, so it cannot be used for PP3.

Sources

Reasoning

PP5 is restricted to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar variation ID 4530535 has no expert-panel submissions in the bundle; its available entries are one-star, single-submitter somatic assertions with non-ACMG labels. PP5 is not met.

Rule

requires exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic

Evidence considered

• For the exact p.Arg479Gln variant, the ClinVar submission audit reports zero expert-panel submissions.
• The available ClinVar submissions are somatic single-submitter assertions (Tier I - Strong, Tier II - Potential, and Oncogenic), not Pathogenic/Likely pathogenic expert-panel classifications.

Sources

Reasoning

The observed gnomAD frequency is far below the generic ACMG/AMP stand-alone benign frequency range; BA1 is not met.

Rule

Generic ACMG/AMP BA1 frequency criterion; no FBXW7-specific specification was available.

Evidence considered

• gnomAD v4.1 reports one allele among 1,612,724 alleles (AF 6.200689e-07); the highest reported population frequency is 8.479520e-07 in non-Finnish Europeans (one allele among 1,179,312).

Still missing

• No FBXW7 disease-specific BA1 threshold was available because no applicable CSPEC/VCEP framework was retrieved.

Sources

Reasoning

The single observed allele is extremely rare and does not provide evidence that its frequency is greater than expected for an FBXW7-associated disorder; BS1 is not met.

Rule

Generic ACMG/AMP BS1 frequency-greater-than-expected criterion; no FBXW7-specific specification was available.

Evidence considered

• gnomAD v4.1 reports total AC 1/AN 1,612,724 (AF 6.200689e-07), with the only population observation in non-Finnish Europeans (AC 1/AN 1,179,312; AF 8.479520e-07).

Still missing

• No FBXW7 disease-specific BS1 maximum credible allele-frequency threshold, prevalence, penetrance, or allelic-heterogeneity calculation was available.

Sources

Reasoning

No homozygotes are reported in gnomAD v4.1, and the case evidence contains no observation of the variant in a documented healthy adult individual. BS2 is not met.

Rule

Generic ACMG/AMP BS2 criterion requires observation in healthy adult individuals for a disorder expected to be fully penetrant early in life.

Evidence considered

• gnomAD v4.1 reports zero homozygotes for the single observed allele.

Still missing

• A disease-appropriate healthy/adult cohort with phenotype and age information was not available.
• The absence of homozygotes is not itself evidence for BS2.

Sources

Reasoning

No functional or biochemical study in the reviewed evidence bundle or full-text publications reports a normal/wild-type-like functional readout for the R479Q variant. On the contrary, all available functional data (PMID:23676439) show a loss of FBXW7 substrate-degradation activity associated with this variant. No basis exists for a benign functional-evidence criterion.

Still missing

• No functional assay data of any kind support a benign/normal-function interpretation for this variant; absence of such data is not equivalent to demonstrating normal function.

Sources

Reasoning

BP1 applies to missense variants in genes for which primarily truncating/loss-of-function variants are the established disease mechanism, making missense changes less likely pathogenic by default. This is the inverse of the FBXW7 mechanism: PMID:23676439 explicitly documents that simple truncating/biallelic LOF mutations are comparatively rare in FBXW7 tumours, while monoallelic missense substitutions at specific propeller-tip arginine residues (including R479) are the predominant, functionally validated oncogenic mechanism. Because missense change -- not truncation -- is the established disease mechanism at this residue/domain, BP1's premise does not hold for this gene, so BP1 is not met.

Evidence considered

• PMID:23676439: 'biallelic, simple loss-of-function mutations are rare; instead, most mutations are monoallelic missense changes involving specific arginine residues at beta-sheet propellor tips' -- directly contradicts the BP1 premise (that truncating variants are the primary disease mechanism) for FBXW7, so BP1 does not apply as a supportive-of-benign call here.

Sources

Reasoning

No gene-specific VCEP framework or CSPEC is available for FBXW7 (generic ACMG/AMP fallback applies). SpliceAI max delta score (0.044) is low and consistent with no splice impact, but this alone is not sufficient to invoke BP4 in the absence of a corroborating missense in-silico signal, and the missense predictor score does not clearly support benign impact either. REVEL score of 0.479 sits in the intermediate/indeterminate zone and does not reach a calibrated benign threshold (REVEL <0.29 is the typical low-end cutoff for benign in silico evidence per ClinGen SVI calibration, PMID 36413997), so REVEL cannot support BP4. BayesDel score (0.0626477) is available but has no verified published threshold/publication for this pipeline, so it is treated as not_available and cannot be used to support BP4 despite the low numeric value. Overall, no calibrated computational predictor meets the threshold to apply BP4.

Evidence considered

• SpliceAI evidence_sentence: 'SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).' Scores: DS_AG=0.044, DS_AL=0.002, DS_DG=0.006, DS_DL=0.0; max_delta_score=0.044 — low splice-impact signal alone does not establish BP4 for a missense variant without a corroborating benign missense predictor signal.
• REVEL score = 0.479 (local REVEL v1.3 lookup); does not meet the ClinGen SVI-calibrated benign threshold (<0.29, PMID 36413997) needed to invoke BP4.
• BayesDel score = 0.0626477 (local BayesDel_170824_noAF lookup), but no verified published calibration threshold/publication is available to this pipeline for BayesDel, so it is treated as not_available for BP4 per pipeline policy.
• No CSPEC/VCEP framework found for FBXW7 (cspec.found=false); final_classification_framework.source='generic_acmg_fallback'.

Still missing

• No gene-specific (VCEP) PP3/BP4 lookup table available for FBXW7 to check for a pre-assigned code.
• BayesDel score is numerically low but lacks a verified published threshold/PMID for this pipeline, so it cannot be used for BP4 despite appearing benign-leaning.
• REVEL score (0.479) is intermediate and does not meet the calibrated benign threshold (<0.29, PMID 36413997).

Sources

Reasoning

BP6 is restricted to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar variation ID 4530535 has no expert-panel submissions in the bundle, and no available submission is a Benign/Likely benign expert-panel classification. BP6 is not met.

Rule

requires exact-variant ClinVar expert-panel classification of Benign or Likely benign

Evidence considered

• For the exact p.Arg479Gln variant, the ClinVar submission audit reports zero expert-panel submissions.
• The available ClinVar submissions are somatic single-submitter assertions and do not include a Benign or Likely benign expert-panel classification.

Sources

Reasoning

PS1 requires a different nucleotide change producing the identical amino acid substitution (p.Arg479Gln) that has already been established as pathogenic/oncogenic by prior independent evidence. No cSpec/VCEP framework exists for FBXW7 (cspec.found=false), so generic ACMG PS1 semantics apply. The pm5_candidates harvesting step (which also covers same-residue/same-change comparator search) explicitly returned found=false and eligible_for_classic_pm5_search=false, meaning no systematic search for alternate codon changes yielding p.Arg479Gln was completed, and no such comparator was surfaced elsewhere in the bundle.

Evidence considered

• pm5_candidates.json reports found=false, pm5_mode=unknown, eligible_for_classic_pm5_search=false, with explicit instruction not to apply PM5/PS1-adjacent same-residue logic from this artifact alone.

Still missing

• No search was performed/returned for other nucleotide substitutions (e.g. NM_033632.3:c.1436G>C or other codon changes) that also yield p.(Arg479Gln) and carry an independent pathogenic/oncogenic classification.
• Cannot apply PS1 without confirming such a comparator variant exists and is independently classified.

Reasoning

No proband-level phenotype, parental genotypes, parentage confirmation, or germline testing result is provided. Therefore, a confirmed de novo occurrence cannot be established under the generic ACMG/AMP framework.

Rule

Generic ACMG/AMP: PS2 requires a de novo variant in an affected individual with maternity and paternity confirmed.

Evidence considered

• No FBXW7 CSPEC/VCEP or local gene-specific framework was retrieved; generic ACMG/AMP assessment applies.
• The consolidated case-evidence bundle provides no individual-level proband, parental, parentage, or germline de novo data for NM_033632.3:c.1436G>A.

Still missing

• Variant result in the affected proband from a germline specimen.
• Targeted parental testing demonstrating absence of NM_033632.3:c.1436G>A in both parents.
• Parentage confirmation and phenotype information sufficient to assess consistency with an FBXW7-associated germline disorder.

Reasoning

PS4 requires statistically significant enrichment of the exact variant in affected individuals relative to appropriate controls. No variant-specific affected-case counts, control comparison, odds ratio, or statistical analysis is available for NM_033632.3:c.1436G>A (p.Arg479Gln), so PS4 cannot be assessed.

Rule

generic ACMG/AMP PS4: statistically significant case-control enrichment or validated affected-case enrichment for the exact variant

Evidence considered

• The consolidated case-evidence bundle contains no variant-specific case-control study, affected-case series with validated enrichment, odds ratio, or p-value for p.Arg479Gln.
• PMID:25768946 was identified as a somatic rhabdomyosarcoma study candidate, but it does not supply an interpretable germline case-control enrichment analysis for the exact variant.

Still missing

• Variant-specific affected-case counts and an appropriate control cohort, with a quantitative enrichment analysis or statistically significant case-control result.

Reasoning

PM3 cannot be assessed. No applicable FBXW7 VCEP/gene-specific specification was retrieved, so the generic ACMG/AMP trans requirement for a recessive disorder applies. The consolidated case evidence contains no affected-proband genotype with a second pathogenic/likely pathogenic allele, no phase result establishing trans configuration, and no established recessive inheritance context for this assessment.

Rule

Generic ACMG/AMP PM3: in a recessive disorder, the variant is observed in trans with a pathogenic variant.

Evidence considered

• The retrieved final classification framework reports no FBXW7-specific VCEP framework and specifies generic ACMG/AMP fallback.
• The gene-context bundle lists no inheritance designation, and the consolidated case materials provide no biallelic affected-proband observation or phase data.

Still missing

• Affected-proband-level genotype data identifying any second FBXW7 variant.
• Phase evidence establishing whether the observed variant and any second pathogenic/likely pathogenic FBXW7 variant are in trans.
• A defined recessive FBXW7 disease context applicable to the proband.

Sources

Reasoning

PM5 requires a different missense change at the same residue (Arg479Xaa, Xaa != Gln) that has been independently established as pathogenic/oncogenic. The dedicated pm5_candidates.json artifact explicitly reports eligible_for_classic_pm5_search=false and found=false, with recommendation.level='not_applicable' and an explicit hermes_instruction not to apply PM5 from that artifact alone. No other alternate-residue-479 substitution with an independent classification was surfaced anywhere in the case bundle (ClinVar, OncoKB, or literature) for this case.

Evidence considered

• pm5_candidates.json: found=false, eligible_for_classic_pm5_search=false, candidate_summary.same_residue_candidates=0, recommendation.level='not_applicable', with explicit instruction to review manually rather than infer PM5 from this artifact.

Still missing

• No systematic ClinVar/literature search for other pathogenic/oncogenic amino-acid substitutions at codon 479 (e.g. p.Arg479Trp, p.Arg479Leu) was completed or returned.
• pm5_candidates.json flags pm5_mode as 'unknown', indicating the harvesting step could not confirm applicability of classic same-residue PM5 semantics for this case; human review needed to search for comparator variants before this criterion can be finalized.

Reasoning

No report documents the variant as de novo in an affected proband, and no parental testing result is supplied. PM6 cannot be assessed.

Rule

Generic ACMG/AMP: PM6 requires an assumed de novo occurrence in an affected individual when parental confirmation is unavailable.

Evidence considered

• No FBXW7 CSPEC/VCEP or local gene-specific framework was retrieved; generic ACMG/AMP assessment applies.
• The consolidated case-evidence bundle provides no individual-level proband or parental testing data for NM_033632.3:c.1436G>A.

Still missing

• A germline proband result and phenotype.
• Parental testing showing the variant absent in both parents, if parentage confirmation is unavailable.

Reasoning

No pedigree, affected or unaffected relative genotypes, phenotypes, or informative meioses are available. Segregation with disease cannot be evaluated.

Rule

Generic ACMG/AMP: PP1 requires co-segregation of the variant with disease in multiple affected family members; strength depends on the amount and quality of segregation evidence.

Evidence considered

• No FBXW7 CSPEC/VCEP or local gene-specific framework was retrieved; generic ACMG/AMP assessment applies.
• The consolidated case-evidence bundle provides no family-level genotype-phenotype segregation data or meiosis count for NM_033632.3:c.1436G>A.

Still missing

• Pedigree with clinical status of relatives.
• Segregation testing for NM_033632.3:c.1436G>A in affected and informative unaffected relatives.
• Number of informative meioses and phenotype definition used for co-segregation analysis.

Reasoning

PP4 requires a patient's phenotype or highly specific clinical findings to be highly specific for a disease associated with FBXW7. The bundle supplies no patient phenotype, diagnostic findings, or phenotype-to-gene-disease comparison; therefore PP4 cannot be assessed.

Rule

generic ACMG/AMP PP4: requires a highly specific patient phenotype for a disease associated with the gene

Evidence considered

• The consolidated case-evidence bundle contains no patient-level phenotype or clinical diagnostic feature set for this variant.
• ClinVar condition labels in the bundle are record-level somatic submissions and do not provide a patient phenotype sufficiently specific to establish PP4.

Still missing

• A documented patient phenotype and a validated comparison showing that the phenotype is highly specific for an FBXW7-associated disease.

Reasoning

No informative non-segregation observation is provided, such as an unequivocally affected relative lacking the variant or an unaffected relative carrying it in a setting where penetrance and age are adequately accounted for.

Rule

Generic ACMG/AMP: BS4 requires lack of segregation between the variant and disease in an informative family, with phenotype definition, age, and penetrance considered.

Evidence considered

• No FBXW7 CSPEC/VCEP or local gene-specific framework was retrieved; generic ACMG/AMP assessment applies.
• The consolidated case-evidence bundle provides no family segregation or non-segregation observations for NM_033632.3:c.1436G>A.

Still missing

• Pedigree and genotype results for informative affected and unaffected relatives.
• Age, phenotype, and penetrance information needed to determine whether any apparent non-segregation is informative.

Reasoning

BP2 cannot be assessed. No applicable FBXW7 VCEP/gene-specific specification was retrieved. The consolidated case evidence contains no individual-level co-occurrence result demonstrating this variant in cis with a pathogenic/likely pathogenic FBXW7 variant, or in trans with such a variant in a fully penetrant dominant disease context. The available ClinVar record is somatic and does not provide usable germline phase or co-occurrence evidence.

Rule

Generic ACMG/AMP BP2: observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observed in cis with a pathogenic variant in any inheritance pattern.

Evidence considered

• The retrieved final classification framework reports no FBXW7-specific VCEP framework and specifies generic ACMG/AMP fallback.
• ClinVar data in the consolidated bundle identify only somatic submissions for this variant; they do not establish germline co-occurrence, phase, unaffected status, or penetrance required for BP2.

Still missing

• Individual-level co-occurrence data for a pathogenic/likely pathogenic FBXW7 variant.
• Validated phase evidence showing cis configuration, or trans configuration in a fully penetrant dominant disease context.
• If trans is proposed, evidence that the relevant FBXW7 disorder is fully penetrant and that the individual is unaffected.

Sources

Reasoning

BP5 requires observation of the variant in a patient whose phenotype is clearly attributable to an alternative molecular basis. No patient-level phenotype, alternative molecular diagnosis, or case observation establishing an independent explanation is provided; therefore BP5 cannot be assessed.

Rule

generic ACMG/AMP BP5: requires an alternative molecular basis explaining the patient's phenotype

Evidence considered

• The consolidated case-evidence bundle contains no patient-level phenotype, alternate molecular diagnosis, or variant-specific BP5 case observation.

Still missing

• A documented affected patient with an independently established alternative molecular cause that clearly explains the phenotype.