No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.FOXL2 encodes a forkhead transcription factor that binds DNA to regulate gene expression, playing an essential role in ovarian development and granulosa cell differentiation. Mutations in this gene cause blepharophimosis syndrome and premature ovarian failure 3. In cancer, FOXL2 acts as a tumor suppressor, inhibiting proliferation and invasion of certain cancer cells, and somatic alterations in the gene are associated with adult granulosa cell tumors.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met (supporting): gnomAD v4.1 frequency 6.2e-07 (1/1,613,972 alleles) is ~1,000-fold below the <0.1% threshold.
Met (supporting): REVEL 0.822 falls within the ClinGen-calibrated PP3 supporting band (0.773-0.931).
No benign criterion marked as applied in the recorded assessment.
With no VCEP or gene-specific framework, generic ACMG/AMP 2015 applies; two supporting criteria (PM2, PP3) satisfy no pathogenic or benign combination, yielding VUS.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 1 / 1,613,972 alleles. Recorded AF 6.19589e-07. Recorded homozygote count 0.
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
A ClinVar laboratory submission summary was not recorded.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FOXL2, a transcription factor, is recurrently mutated in adult granulosa cell tumors.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 9 not met · 12 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Framework: no ClinGen CSPEC/VCEP specification exists for FOXL2 in this case (cspec found=false; vcep_materials empty; gene_vcep_dir null); generic ACMG/AMP 2015 (PMID 25741868) governs this group.
Variant NM_023067.4:c.386C>T (NP_075555.1:p.Thr129Met) is a missense change at FOXL2 codon 129 (ACG>ATG).
No same-residue or same-amino-acid comparator evidence exists: the variant is absent from ClinVar, the literature pass returned zero PMIDs, and pm5_candidates contains no candidates (automatic harvesting skipped). PS1 is not met; PM5 is not assessable.
PM1 is not assessable: the CancerHotspots query was negative (hotspot prong) and no domain boundary annotation is present in the bundle to evaluate the critical-functional-domain prong; human review of forkhead domain membership of residue 129 is needed.
PP2 is not assessable: no FOXL2 missense constraint metrics are present in the bundle; gene-level literature suggests missense is a disease mechanism but cannot be cited as variant-specific evidence.
BP1 is not met: FOXL2 disease mechanism includes missense variants (dominant C-terminal missense variants in non-syndromic POF; oncogenic p.C134W; BPES germline variant spectrum), contradicting the 'primarily truncating variants' premise.
No criterion in this group is met; no strength is assigned to any criterion.
No ClinGen CSPEC or VCEP specification exists for FOXL2 (cspec.found=false, gene_vcep_dir=null, vcep_materials.json empty); per governing-framework precedence, the generic ACMG/AMP 2015 framework (Richards et al., PMID 25741868) applies to this group.
All four segregation/de novo criteria (PS2, PM6, PP1, BS4) require proband, parental testing, family segregation, or non-segregation observations. The consolidated case bundle contains none of these for NM_023067.4:c.386C>T: no proband genotype, no parental tests, no pedigree/meioses, no affected or unaffected relatives tested.
The variant is absent from ClinVar (no submissions) and literature_pass.json found 0 PMIDs; the publications/ directory is empty and fulltext_map.json is {}, so no published de novo, segregation, or non-segregation report exists to screen for this exact variant.
Consequently PS2, PM6, PP1, and BS4 are all returned as not_assessed; the sole gap is absence of family/parental testing data, which no available source can fill.
The single gnomAD v4.1 allele (AF 6.2e-07, 0 homozygotes) was considered but is population-frequency data, not family non-segregation evidence, and cannot support BS4.
No ClinGen CSPEC/VCEP and no local gene-specific framework exists for FOXL2 (framework_mode=generic_acmg, framework_complete=false, precedence_rank=3); the generic ACMG/AMP 2015 rules (PMID:25741868, source_registry key generic_acmg_combination_rules) govern PS3/BS3.
PS3 is not_assessed: no well-established functional studies demonstrating a deleterious effect of c.386C>T (p.Thr129Met) exist in the case evidence (0 PMIDs in literature_pass, empty fulltext_map, variant absent from ClinVar, OncoKB not reviewed, COSMIC no result). The criterion contributes no pathogenic evidence.
BS3 is not_assessed: no well-established functional studies demonstrating no damaging effect exist; the in silico SpliceAI max delta of 0.00 is not a functional study and cannot satisfy BS3. The criterion contributes no benign evidence.
Neither criterion is met; both remain open gaps pending variant-specific functional assay data.
Governing framework: no ClinGen CSPEC/VCEP specification exists for FOXL2 (vcep_materials.json: 'no cspec url available'; final_classification_framework found = false, precedence_rank 3). Generic ACMG/AMP 2015 (PMID 25741868) applies.
PS4 (case-control enrichment): not assessed - zero literature PMIDs and no case-control/case-cohort data for c.386C>T; enrichment cannot be confirmed or refuted.
PP4 (phenotype specificity): not assessed - no clinical phenotype documented for any carrier of c.386C>T; OncoKB gene-level somatic context is not variant-specific and was not used.
PP5/BP6 (expert-panel ClinVar assertions): not met - the variant is absent from ClinVar, so no exact-variant expert-panel (3-star) classification exists to trigger either criterion.
BP5 (alternative molecular basis): not assessed - no proband-level reports of this variant with an alternative genetic cause identified.
gnomAD v4.1 single allele (AF 6.2e-07, 0 homozygotes) and absence from gnomAD v2.1 were noted but are population-frequency evidence belonging to prevalence/BA1-BS1-PM2 adjudication, not to this group's criteria.
Allelic criteria contribute no pathogenic or benign evidence: PM3 is not applicable because FOXL2 germline disease (BPES) is autosomal dominant and no trans observation with a pathogenic variant exists; BP2 is not met because no pathogenic variant was observed in trans or cis with c.386C>T.
The variant has no clinical observations at all (absent from ClinVar; 0 PMIDs in literature pass; single unphased gnomAD v4.1 heterozygote), so phase-based (PM3) and cis/trans-based (BP2) evidence cannot be established from any source.
Framework: no FOXL2 CSPEC/VCEP specification was retrieved (cspec.found=false; vcep_materials final_classification_framework.found=false); generic ACMG/AMP 2015 applies (Richards et al., PMID 25741868; source_registry key generic_acmg_combination_rules).
Variant NM_023067.4:c.386C>T is a missense change (NP_075555.1:p.(Thr129Met), exon 1); both splice-impact (SpliceAI) and missense in-silico (REVEL, BayesDel) sub-paths were evaluated for PP3/BP4; no double-counting of a prediction across PP3/BP4/BP7.
PP3: met at supporting strength. REVEL 0.822 >= 0.773, the ClinGen SVI-calibrated PP3 supporting threshold (Pejaver et al., PMID 36413997), and < 0.932 (strong). SpliceAI max delta 0.00 gives no splice-impact support. BayesDel 0.221987 excluded (no verified published threshold).
BP4: not met. The only calibrated missense predictor (REVEL 0.822) supports a damaging effect and contradicts BP4; SpliceAI no-splice-impact is a single splice-only line and insufficient alone; BayesDel excluded as uncalibrated.
No literature PMIDs were retrieved for this case (literature_pass.json total_pmids = 0; fulltext_map.json empty); no case publications were available to review in the publications directory.
No ClinGen CSPEC/VCEP specification exists for FOXL2 (vcep_materials: no cspec url available; case framework_mode = generic_acmg; final_classification_framework precedence_rank 3). Population criteria were therefore adjudicated under generic ACMG/AMP 2015 rules (PMID 25741868, generic_acmg_combination_rules) with the pipeline global gnomAD non-VCEP thresholds (PM2<0.1%, BS1>0.3%, BA1>1%).
Population data: gnomAD v4.1 total AF 6.1959e-07 (1/1,613,972 alleles), highest subpopulation NFE AF 8.4748e-07 (1/1,179,968), 0 homozygotes in all populations; variant absent from gnomAD v2.1 and gnomAD-Canada v1.0; absent from ClinVar and COSMIC; no PMIDs identified in the literature pass.
BA1 not met (max AF 0.00008% is orders of magnitude below the >5% stand-alone and >1% pipeline thresholds); BS1 not met (AF far below the >0.3% threshold and not greater than expected for the rare autosomal dominant disorder BPES); BS2 not met (single gnomAD heterozygote lacks phenotype confirmation of unaffected adult status; 0 homozygotes).
PM2 met at supporting strength: AF ~3 orders of magnitude below the <0.1% threshold, with absence across gnomAD v2.1, gnomAD-Canada v1.0, and ClinVar.
No criteria match.
The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0 and is present in gnomAD v4.1 at only 1/1,613,972 alleles (total AF 6.1959e-07; highest subpopulation AF 8.4748e-07 = 0.00008%, NFE) with 0 homozygotes in all populations; it is also absent from ClinVar. This is approximately three orders of magnitude below the PM2 threshold of <0.1% (pipeline global gnomAD non-VCEP threshold), consistent with 'absent or extremely low frequency in population databases' for a dominant disorder. PM2 is met and applied at supporting strength (PM2_supporting).
PM2: absent from controls / extremely low population frequency (Richards et al. 2015, PMID 25741868); pipeline non-VCEP global threshold PM2<0.1%. Applied at supporting strength (PM2_supporting).
Missense in-silico sub-path: REVEL score 0.822 for NM_023067.4:c.386C>T (p.Thr129Met) meets the ClinGen SVI-calibrated PP3 supporting threshold of REVEL >= 0.773 (Pejaver et al., Am J Hum Genet 2022;109(12):2163-2177, PMID 36413997); 0.822 falls in the supporting band (0.773-0.931) and is below the PP3 strong threshold of 0.932, so PP3 is met at supporting strength. Splice-impact sub-path: SpliceAI max delta score 0.00 (DS_AG/DS_AL/DS_DG/DS_DL all 0.0) predicts no splice impact and does not contribute to PP3. BayesDel score 0.221987 was retrieved but is excluded because no verified published calibration threshold is available to this pipeline (treated as insufficiently calibrated). aGVGD was not available for this case. Per ClinGen SVI tool-calibration practice, a single calibrated predictor may be applied at its calibrated strength; no double-counting across PP3/BP4/BP7 is performed.
PP3 (ACMG/AMP 2015, Richards et al., PMID 25741868): multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.); applied at strength calibrated by the ClinGen SVI computational-evidence recommendations (Pejaver et al., PMID 36413997).
PS1 requires the same amino acid change (p.Thr129Met) to be established as pathogenic in a previously reported variant, regardless of the nucleotide change. No such established variant exists in any consulted source: the variant is absent from ClinVar (all query strategies returned no variation IDs or submissions), the literature pass returned zero PMIDs, and the pm5_candidates artifact contains no candidates. Additionally, codon 129 in NM_023067.4 is ACG, and the only single-nucleotide substitution in that codon that yields methionine is c.386C>T itself (c.385A>G/A>C/A>T give Ala/Pro/Ser; c.386C>A/C>G give Lys/Arg; c.387G>A/C/T are synonymous Thr), so no alternative nucleotide change could independently establish the same amino acid change. The amino acid change is therefore not established as pathogenic; PS1 is not met.
PS1: Same amino acid change as a previously established pathogenic variant regardless of nucleotide change (Richards et al. 2015, PMID 25741868).
PP5 is applied only when an exact-variant ClinVar expert-panel (3-star) classification of Pathogenic or Likely pathogenic exists. This variant is absent from ClinVar: prefetch queried multiple search terms (FOXL2[GENE] AND c.386C>T[VARNAME], NM_023067.4:c.386C>T, NC_000003.11:g.138665179G>A, and others), exact_match = false, variation_ids = [], and the evidence pass returned 'no_result'. With no ClinVar record at all, no expert-panel Pathogenic/LP classification exists, so the PP5 trigger cannot be satisfied. Ordinary laboratory or aggregate ClinVar labels would in any case not be permitted to trigger PP5.
Pipeline policy: PP5 applies only for an exact-variant ClinVar expert-panel (3-star) Pathogenic/Likely pathogenic classification; no such classification exists for this variant
Highest observed allele frequency is 8.474806096436513e-07 (0.00008%, 1/1,179,968 alleles) in European (non-Finnish) in gnomAD v4.1; total AF is 6.195894352566215e-07 (1/1,613,972 alleles), and the variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0. This is several orders of magnitude below the BA1 stand-alone threshold of >5% (Richards et al. 2015, PMID 25741868) and also far below the more permissive pipeline global gnomAD non-VCEP BA1 threshold of >1%. BA1 is not met.
BA1: allele frequency >5% in a reference population (Richards et al. 2015, PMID 25741868); pipeline non-VCEP global threshold >1%. Observed max AF 8.47e-07 does not approach either threshold.
Highest observed allele frequency (NFE 8.4748e-07, 0.00008%) is far below the BS1 threshold of >0.3% (pipeline global gnomAD non-VCEP threshold) and is not greater than expected for FOXL2-associated blepharophimosis-ptosis-epicanthus inversus syndrome (BPES), a rare autosomal dominant disorder with high penetrance of the eyelid phenotype. The observed frequency is orders of magnitude lower than a plausible disease allele frequency for BPES. BS1 is not met.
BS1: allele frequency greater than expected for the disorder (Richards et al. 2015, PMID 25741868); pipeline non-VCEP global threshold BS1>0.3%. Observed max AF 8.47e-07 is far below.
BS2 requires observation of the variant in a healthy adult individual (heterozygous for a dominant disorder such as BPES). gnomAD v4.1 contains a single heterozygous allele (1/1,613,972; NFE) with 0 homozygotes in every population, and gnomAD does not provide phenotype confirmation that the carrier is an unaffected adult; a single reference-population observation without clinical phenotype data cannot establish BS2. The variant is absent from gnomAD v2.1, gnomAD-Canada v1.0, and ClinVar. BS2 is not met.
BS2: observed in a healthy adult individual for a dominant disorder with full penetrance expected at an early age (Richards et al. 2015, PMID 25741868). A single gnomAD heterozygote without phenotype confirmation is insufficient.
BP1 applies only when primarily truncating variants are known to cause disease in the gene. For FOXL2 this premise is contradicted by the gene-level evidence in the case bundle: FOXL2 germline variants cause autosomal dominant blepharophimosis-ptosis-epicanthus inversus syndrome (BPES) with a variant spectrum that includes missense changes, dominant C-terminal rare missense FOXL2 variants are an established cause of non-syndromic primary ovarian failure (PMID 38558253), the FOXL2 missense change p.C134W is a recurrent oncogenic driver in adult granulosa cell tumors and is dominant for eyelid hypoplasia in a mouse model (PMID 36409821, and OncoKB gene-level context noting FOXL2 is recurrently mutated in AGCT), and >100 germline FOXL2 variants are associated with BPES (PMID 34727551). Because missense variants are known to cause FOXL2 disease, BP1 is not met. Note: these sources support the gene-level conclusion only and do not mention p.Thr129Met.
BP1: Missense variant in a gene for which primarily truncating variants are known to cause disease (Richards et al. 2015, PMID 25741868).
BP2 (Richards et al. 2015, PMID 25741868) requires observing this variant in trans with a pathogenic variant for a fully penetrant dominant gene, or in cis with a pathogenic variant in any inheritance pattern. No such observation exists anywhere in the collected evidence: the variant is absent from ClinVar; no proband, family, or segregation data were retrieved; the literature pass returned 0 PMIDs; and gnomAD v4.1 shows only a single heterozygous carrier (1/1,613,972 alleles, AF 6.2e-07, 0 homozygotes) with no second FOXL2 variant genotyped and no phase information. There is therefore no evidence of a pathogenic variant in trans or cis with c.386C>T, and BP2 is not met. This is an absence-of-evidence determination, not evidence of benignity.
BP2 (Richards et al. 2015, PMID 25741868): 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. No such observation is present in this case.
BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. No such evidence exists here: (1) the only calibrated missense predictor, REVEL (0.822), exceeds the PP3 supporting threshold of 0.773 (PMID 36413997) and therefore predicts a damaging effect, directly contradicting BP4; (2) BayesDel (0.221987) is excluded as insufficiently calibrated (no verified published threshold); (3) SpliceAI max delta score 0.00 indicates no predicted splice impact, but for a missense variant this is a single splice-only line and cannot by itself satisfy BP4, which requires multiple lines of computational evidence of no impact. BP4 is therefore not met.
BP4 (ACMG/AMP 2015, Richards et al., PMID 25741868): multiple lines of computational evidence suggest no impact on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP6 is applied only when an exact-variant ClinVar expert-panel (3-star) classification of Benign or Likely benign exists. This variant is absent from ClinVar (no variation IDs; multiple search terms all returned no exact match; evidence pass search_status = 'no_result'). No expert-panel Benign/LB classification exists, so the BP6 trigger cannot be satisfied. Non-expert submissions would never trigger BP6 regardless.
Pipeline policy: BP6 applies only for an exact-variant ClinVar expert-panel (3-star) Benign/Likely benign classification; no such classification exists for this variant
PS2 (de novo, maternity and paternity confirmed; strong) requires documentation that the variant arose de novo in the proband with confirmed biological parentage. The case bundle contains no proband genotype data, no parental testing results, and no maternity/paternity confirmation for NM_023067.4:c.386C>T (p.Thr129Met) in FOXL2. The variant is absent from ClinVar (registry key: clinvar; no submissions exist), so no curated de novo record is available, and literature_pass.json returned total_pmids=0, so no published de novo report could be screened. No CSPEC/VCEP exists for FOXL2; the generic ACMG/AMP 2015 framework (PMID 25741868) applies, but no evidence exists to trigger PS2. Criterion not assessed because the required parental-testing evidence is entirely absent from the case.
PS2 (Richards et al. 2015, PMID 25741868, generic ACMG/AMP): 'De novo (maternity and paternity confirmed)' — Strong. Requires confirmed de novo occurrence; inapplicable without parental testing data.
PS3 (Richards et al. 2015, PMID:25741868) requires well-established functional studies demonstrating a deleterious effect of the variant. For NM_023067.4:c.386C>T (p.Thr129Met) in FOXL2, no variant-specific functional assay evidence exists anywhere in this case: literature_pass.json surfaced 0 PMIDs, fulltext_map.json is empty, the variant is absent from ClinVar (no functional submissions), OncoKB explicitly reports no variant-specific reviewed functional evidence ('Unknown Oncogenic Effect', not_reviewed=true), COSMIC has no record, and CancerHotspots shows no hotspot row. All five gene-context publications available in the case (pvs1_gene_context supporting papers) were screened and none mentions p.Thr129Met; the closest functional study (PMID:36409821) investigates the different somatic variant C134W (c.402C>G) in a mouse model. In silico predictions (SpliceAI max delta 0.00, REVEL 0.822, BayesDel 0.221987) are not functional studies and cannot satisfy PS3. Because no functional evidence is available at all, the criterion cannot be assessed; the gap is a validated functional assay for p.Thr129Met (e.g., FOXL2 transcriptional activation reporter assay, protein stability/expression, subcellular localization). Governing framework: no ClinGen CSPEC/VCEP or local gene-specific framework exists for FOXL2, so the generic ACMG/AMP 2015 definition applies.
ACMG/AMP 2015 PS3 (Richards et al. 2015, PMID:25741868)
PS4 requires the variant to be significantly enriched in affected individuals versus controls in a case-control or case-cohort study. No such data exist for FOXL2 c.386C>T: the literature pass returned 0 PMIDs across all evidence sources, the variant is absent from ClinVar and COSMIC, and no published case series or cohort reporting this variant was identified. Absence of enrichment evidence is a data gap, not evidence of no enrichment, so PS4 cannot be adjudicated as met or not met.
Generic ACMG/AMP 2015 PS4 (source_registry: generic_acmg_combination_rules, PMID 25741868); no FOXL2 CSPEC/VCEP exists so generic fallback applies
PM1 has two prongs. Hotspot prong: the CancerHotspots query for 'FOXL2 T129' returned no statistically significant hotspot (descriptive bundle evidence only; no source_registry key exists for 'hotspots'), and the variant is also absent from COSMIC. Domain prong: the case bundle contains no residue-level functional-domain annotation for FOXL2 (gene_context_FOXL2.json is a one-line summary; pvs1_gene_context addresses LoF mechanism, not domains), so membership of residue 129 in a critical functional domain cannot be established from the evidence bundle. The consulted literature shows FOXL2 germline disease variants and the recurrent somatic oncogenic p.C134W localize to the forkhead (DNA-binding) region, and residue 129 lies near the commonly annotated N-terminal boundary of the forkhead domain, but this is not documented in any bundle source and cannot be cited. PM1 is therefore not assessable without human domain review.
PM1: Located in a mutational hot spot and/or critical and well-established functional domain (e.g., active site of an enzyme) without benign variation (Richards et al. 2015, PMID 25741868).
PM5 requires a different missense change at the same residue (codon 129) that has been determined pathogenic. The pm5_candidates artifact found no candidates (found=false, 0 same-residue candidates) and explicitly skipped automatic same-residue harvesting (pm5_mode 'unknown', eligible_for_classic_pm5_search=false). ClinVar is empty for this variant, and no literature PMIDs were retrieved. No alternate missense change at residue 129 (e.g., p.Thr129Lys/Arg/Ala/Pro/Ser) is reported in any consulted source, so PM5 cannot be evaluated with the current evidence base.
PM5: Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before (Richards et al. 2015, PMID 25741868).
PM6 (assumed de novo without confirmation of maternity and paternity; moderate) requires evidence that the variant is de novo but with parentage unconfirmed. The case bundle contains no proband genotype data and no parental testing results at all for NM_023067.4:c.386C>T (p.Thr129Met), so there is no basis for even an unconfirmed de novo assertion. The variant is absent from ClinVar (registry key: clinvar) and literature_pass.json found 0 PMIDs, so no published or curated 'assumed de novo' report is available. Generic ACMG/AMP 2015 (PMID 25741868) governs (no FOXL2 CSPEC/VCEP), but no evidence exists to trigger PM6. Criterion not assessed because no de novo evidence of any kind is present.
PM6 (Richards et al. 2015, PMID 25741868, generic ACMG/AMP): 'Assumed de novo, but without confirmation of paternity and maternity' — Moderate. Requires an unconfirmed de novo observation; no such data present.
PP1 (co-segregation with disease in affected family members; supporting) requires segregation data showing the variant tracks with the phenotype across affected relatives. The case bundle contains no family pedigree, no segregation data, and no affected relatives tested for NM_023067.4:c.386C>T (p.Thr129Met) in FOXL2. The variant is absent from ClinVar (registry key: clinvar), and literature_pass.json returned total_pmids=0, so no published co-segregation record could be screened. Generic ACMG/AMP 2015 (PMID 25741868) governs (no FOXL2 CSPEC/VCEP). Criterion not assessed because no meioses or segregation observations exist in the case.
PP1 (Richards et al. 2015, PMID 25741868, generic ACMG/AMP): 'Co-segregation with disease in affected family members in multiple affected family members' — Supporting. Requires segregation observations; none present.
PP2 requires (1) a gene with a low rate of benign missense variation and (2) missense variants as a common mechanism of disease. Prong 1 cannot be evaluated: no gene-level missense constraint metrics (e.g., gnomAD missense Z-score or observed-vs-expected ratio) are present in the case bundle, and the HCI prior lookup was not found (gene not supported). Prong 2 is suggested by gene-level literature in the case (dominant C-terminal rare missense FOXL2 variants cause non-syndromic primary ovarian failure, PMID 38558253; >100 germline FOXL2 variants are associated with BPES, PMID 34727551), but those records are abstract-only, do not mention p.Thr129Met, and cannot serve as variant-specific citations. Because the constraint prong is unsupported by any citable evidence in the bundle, PP2 is not assessed.
PP2: Missense variant in a gene that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease (Richards et al. 2015, PMID 25741868).
PP4 requires the patient's phenotype to be highly specific for a gene with a single genetic etiology, or the variant to be observed in multiple unrelated individuals with the established phenotype. No clinical phenotype data for any individual carrying FOXL2 c.386C>T are available (no PMIDs, no ClinVar record, no case reports). OncoKB provides only gene-level somatic context (FOXL2 recurrently mutated in adult granulosa cell tumors) with the variant explicitly 'Unknown Oncogenic Effect' and not reviewed; this is neither variant-specific nor germline phenotype evidence and was not used. Germline FOXL2 phenotypes (BPES, primary ovarian insufficiency) are not documented for any carrier of this variant, so PP4 cannot be evaluated.
Generic ACMG/AMP 2015 PP4 (source_registry: generic_acmg_combination_rules, PMID 25741868); no FOXL2 CSPEC/VCEP exists so generic fallback applies
BS3 (Richards et al. 2015, PMID:25741868) requires well-established functional studies demonstrating no damaging effect on protein function or splicing. No such studies exist for NM_023067.4:c.386C>T (p.Thr129Met) in any case source: literature_pass.json surfaced 0 PMIDs, fulltext_map.json is empty, the variant is absent from ClinVar, OncoKB provides no reviewed functional evidence, COSMIC has no record, and none of the five available gene-context publications mentions p.Thr129Met. The only splicing-relevant datum is SpliceAI (max delta score 0.00), which is an in silico splicing prediction, not a well-established functional study, and is therefore insufficient for BS3 (and does not speak to protein function at all). Because no functional assay demonstrates a lack of damaging effect, BS3 cannot be assessed; the gap is a validated assay showing no damaging effect (e.g., minigene splicing assay or FOXL2 transcriptional activity assay with appropriate positive/negative controls). Governing framework: no ClinGen CSPEC/VCEP or local gene-specific framework exists for FOXL2, so the generic ACMG/AMP 2015 definition applies.
ACMG/AMP 2015 BS3 (Richards et al. 2015, PMID:25741868)
BS4 (non-segregation with disease; strong) requires evidence that the variant is absent in an affected family member (or present in unaffected individuals) demonstrating non-segregation. The case bundle contains no family testing data whatsoever for NM_023067.4:c.386C>T (p.Thr129Met) in FOXL2: no affected relatives tested, no unaffected relatives tested, no pedigree. The variant is absent from ClinVar (registry key: clinvar), and literature_pass.json returned total_pmids=0, so no published non-segregation report could be screened. Note: the single gnomAD v4.1 allele (AF 6.2e-07, registry key: gnomad_v4) is a population-frequency observation and does not constitute BS4 family non-segregation evidence. Generic ACMG/AMP 2015 (PMID 25741868) governs (no FOXL2 CSPEC/VCEP). Criterion not assessed because no non-segregation evidence is present.
BS4 (Richards et al. 2015, PMID 25741868, generic ACMG/AMP): 'Non-segregation with disease' — Strong. Requires family-based non-segregation observations; none present.
BP5 requires a proband with the relevant phenotype in whom an alternative molecular basis for the disease has been identified (e.g., a pathogenic variant in another gene). No proband-level data are available for FOXL2 c.386C>T: no literature reports, no ClinVar record, and no clinical case descriptions that document both the variant and an alternative genetic cause. The criterion therefore cannot be evaluated either way.
Generic ACMG/AMP 2015 BP5 (source_registry: generic_acmg_combination_rules, PMID 25741868); no FOXL2 CSPEC/VCEP exists so generic fallback applies
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_023067.4:c.386C>T in FOXL2 is a missense substitution predicted to produce NP_075555.1:p.(Thr129Met). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_null_variant_class
PM3 (Richards et al. 2015, PMID 25741868) is defined for recessive disorders only: 'For recessive disorders, detected in trans with a pathogenic variant.' FOXL2 germline disease (blepharophimosis, ptosis, epicanthus inversus syndrome, BPES) is an autosomal dominant condition, as stated in the abstracts of PMID 34727551 and PMID 38558253 retrieved within pvs1_gene_context. The variant under review (NM_023067.4:c.386C>T, p.Thr129Met) has no observations in any clinical source: it is absent from ClinVar, the literature pass returned 0 PMIDs, and no compound-heterozygous, homozygous, or phased (trans) observation with any pathogenic FOXL2 allele exists. Because the disease context is dominant and no recessive-disease allele configuration was observed, PM3 is not applicable in this case. Even if a recessive context were entertained hypothetically, the absence of any observed pathogenic variant in trans would leave PM3 unmet.
PM3 (Richards et al. 2015, PMID 25741868): For recessive disorders, detected in trans with a pathogenic variant. Not applicable here because FOXL2 germline disease (BPES) is autosomal dominant and no trans observation exists.
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_023067.4:c.386C>T in FOXL2 is a missense substitution predicted to produce NP_075555.1:p.(Thr129Met). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_023067.4:c.386C>T in FOXL2 is a missense substitution predicted to produce NP_075555.1:p.(Thr129Met). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_023067.4:c.386C>T in FOXL2 is a missense substitution predicted to produce NP_075555.1:p.(Thr129Met). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
Every interpreted variant in FOXL2, mapped onto the exon structure of NM_023067.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| European (non-Finnish)1 / 1,179,968 | 8.5e-07 |
This variant is present in gnomAD v4.1 (AF= 6.19589e-07; MAF= 0.00006%, 1/1613972 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47481e-07; MAF= 0.00008%, 1/1179968 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
Missense in-silico sub-path: REVEL score 0.822 for NM_023067.4:c.386C>T (p.Thr129Met) meets the ClinGen SVI-calibrated PP3 supporting threshold of REVEL >= 0.773 (Pejaver et al., Am J Hum Genet 2022;109(12):2163-2177, PMID 36413997); 0.822 falls in the supporting band (0.773-0.931) and is below the PP3 strong threshold of 0.932, so PP3 is met at supporting strength. Splice-impact sub-path: SpliceAI max delta score 0.00 (DS_AG/DS_AL/DS_DG/DS_DL all 0.0) predicts no splice impact and does not contribute to PP3. BayesDel score 0.221987 was retrieved but is excluded because no verified published calibration threshold is available to this pipeline (treated as insufficiently calibrated). aGVGD was not available for this case. Per ClinGen SVI tool-calibration practice, a single calibrated predictor may be applied at its calibrated strength; no double-counting across PP3/BP4/BP7 is performed.
PP3 (ACMG/AMP 2015, Richards et al., PMID 25741868): multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.); applied at strength calibrated by the ClinGen SVI computational-evidence recommendations (Pejaver et al., PMID 36413997).
BP4 requires multiple lines of computational evidence suggesting no impact on the gene or gene product. No such evidence exists here: (1) the only calibrated missense predictor, REVEL (0.822), exceeds the PP3 supporting threshold of 0.773 (PMID 36413997) and therefore predicts a damaging effect, directly contradicting BP4; (2) BayesDel (0.221987) is excluded as insufficiently calibrated (no verified published threshold); (3) SpliceAI max delta score 0.00 indicates no predicted splice impact, but for a missense variant this is a single splice-only line and cannot by itself satisfy BP4, which requires multiple lines of computational evidence of no impact. BP4 is therefore not met.
BP4 (ACMG/AMP 2015, Richards et al., PMID 25741868): multiple lines of computational evidence suggest no impact on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_023067.4:c.386C>T in FOXL2 is a missense substitution predicted to produce NP_075555.1:p.(Thr129Met). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication, because no structured VCEP criteria-combination framework governs this case (framework_complete=false); the generic ACMG/AMP 2015 fallback applies.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.822. BayesDel score = 0.221987.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 6.19589e-07; MAF= 0.00006%, 1/1613972 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47481e-07; MAF= 0.00008%, 1/1179968 alleles, homozygotes = 0).
Absent from gnomAD v2.1.
Absent from gnomAD-Canada v1.0.
This variant is absent from ClinVar.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.822. BayesDel score = 0.221987.
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FOXL2, a transcription factor, is recurrently mutated in adult granulosa cell tumors.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.