About FOXL2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FOXL2 c.297_311del, p.(Gln99_Arg103del)
Classification
Uncertain significance
Variant description:
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.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 2
Benign evidence criteria: 0
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting
NM_023067.4:c.297_311del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP 2015, absence from population databases supports pathogenicity at a supporting level (allele frequency < 0.1%).
PM4Moderate
PM4 · moderate
NM_023067.4:c.297_311del is an in-frame deletion removing 15 nucleotides and 5 amino acids (p.Gln99_Arg103del) in exon 1 of FOXL2. The deletion occurs in a non-repeat region of the gene — it lies upstream of the polyalanine tract at residues 221-234 and is distinct from the poly-glycine (residues ~57-68) and poly-proline (residues 88-99) tracts. In-frame deletions in non-repeat regions that alter protein length are considered moderate evidence of pathogenicity under generic ACMG/AMP 2015.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PM4 moderate; combination = 1 moderate + 1 supporting, which maps to VUS.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement 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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 20 not met · 0 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_023067.4:c.297_311del (p.Gln99_Arg103del) is an in-frame deletion of 15 nucleotides in exon 1 of FOXL2, removing five amino acids (Q99-R103) in a non-repeat region of the gene. Under generic ACMG/AMP 2015, this qualifies for PM4 at moderate strength.
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the <0.1% allele frequency threshold for PM2 at supporting level.
PVS1 is not met: the variant is an in-frame deletion that does not fall into the default null-variant buckets under PMC6185798 (nonsense, frameshift, or canonical splice). The pvs1_variant_assessment confirms generic PVS1 is not applicable.
No functional studies, de novo data, cosegregation data, case-control data, computational evidence of deleteriousness, or ClinVar classification are available for this variant.
Total evidence: 1 moderate (PM4) + 1 supporting (PM2). Under ACMG/AMP 2015 combination rules (PMID:25741868), this is insufficient for likely pathogenic (which requires ≥2 moderate or ≥1 moderate + ≥2 supporting). The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_023067.4:c.297_311del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP 2015, absence from population databases supports pathogenicity at a supporting level (allele frequency < 0.1%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0 (genomes)
Sources
PM4 ModerateNM_023067.4:c.297_311del is an in-frame deletion removing 15 nucleotides and 5 amino acids (p.Gln99_Arg103del) in exon 1 of FOXL2. The deletion occurs in a non-repeat region of the gene — it lies upstream of the polyalanine tract at residues 221-234 and is distinct from the poly-glycine (residues ~57-68) and poly-proline (residues 88-99) tracts. In-frame deletions in non-repeat regions that alter protein length are considered moderate evidence of pathogenicity under generic ACMG/AMP 2015. Details ▾Hide ▴
Evidence considered
- In-frame deletion of 15 bp removing 5 amino acids (Q99-R103)
- Confirmed non-repeat region: not within polyalanine (221-234)
- poly-glycine
- or poly-proline tracts
Not met · 20 · evaluated, threshold not reached
PVS1 NM_023067.4:c.297_311del is an in-frame deletion of 15 nucleotides in exon 1, predicted to remove 5 amino acids (p.Gln99_Arg103del) without disrupting the reading frame. This variant does not fall into the default PVS1 null-variant buckets defined by PMC6185798 (nonsense, frameshift, or canonical ±1,2 splice consensus variants). The pvs1_variant_assessment confirms apply_generic_pvs1_framework is false and variant_bucket is 'other'. While FOXL2 loss-of-function is a known mechanism for blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES), this specific in-frame deletion does not meet PVS1 criteria. Details ▾Hide ▴
Evidence considered
- In-frame deletion of 15 bp in exon 1
- not a null variant
- pvs1_variant_assessment: apply_generic_pvs1_framework=false
- variant_bucket='other'
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PS2 No de novo data are available for NM_023067.4:c.297_311del. PS2 requires confirmation that the variant occurred de novo with confirmed maternity and paternity in a patient with a phenotype consistent with the gene. Details ▾Hide ▴
Still missing
- No de novo testing data available for this variant
PS3 No functional studies have been identified for NM_023067.4:c.297_311del (p.Gln99_Arg103del). OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. No literature reports experimental characterization of this specific variant or a systematically characterized range that includes residues Q99-R103. Domain-level inference from sparse testing of nearby residues does not satisfy PS3 requirements. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional data
- No publications identified with functional data for this variant or systematically characterized range
Still missing
- No functional studies available for residues Q99-R103 or a systematically characterized range including them
Sources
PS4 No case-control or prevalence data are available for this variant. It is absent from ClinVar and all queried population databases, providing no evidence of enrichment in affected individuals relative to controls. Details ▾Hide ▴
Still missing
- No affected-vs-control prevalence data available
PM1 The deleted region (residues Q99-R103) lies in the N-terminal region of FOXL2 outside well-characterized functional domains such as the forkhead DNA-binding domain (residues ~151-250). Cancerhotspots.org does not identify a statistically significant hotspot at this position. While the N-terminal region contributes to transcriptional regulation, the specific 5-residue segment Q99-R103 has not been characterized as a critical, well-established functional domain without benign variation sufficient to satisfy PM1. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: no significant hotspot at this position
- Deleted region is outside the forkhead DNA-binding domain (~151-250)
Still missing
- No crystal structure or domain characterization specifically defining residues Q99-R103 as a critical functional domain
PM6 No de novo confirmation data are available for this variant. PM6 requires a de novo observation without confirmation of paternity and maternity. No published or database reports of de novo occurrence were identified. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 No cosegregation data are available for NM_023067.4:c.297_311del. PP1 requires demonstration that the variant cosegregates with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No family cosegregation data available
PP3 No computational evidence supports a deleterious effect for this variant. SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not applicable to insertion-deletion variants. HCI prior scores are not available for FOXL2. Without multiple concordant in silico predictions of deleteriousness, PP3 cannot be applied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no splice impact)
- REVEL/BayesDel not available for indels
- HCI prior not available for FOXL2
Still missing
- No in silico protein-level predictors available for in-frame deletions
Sources
PP4 No patient phenotype data are available for comparison to the FOXL2-associated disease spectrum (blepharophimosis, ptosis, epicanthus inversus syndrome / BPES; premature ovarian insufficiency). PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Still missing
- No patient phenotype information provided
PP5 NM_023067.4:c.297_311del is absent from ClinVar with no classification from any submitter, including expert panels. PP5 requires that a reputable source has previously reported the variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: absent
- no classification available
Still missing
- No prior classification from any reputable source
Sources
BA1 NM_023067.4:c.297_311del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency > 1% in any population database, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = 0)
- Absent from gnomAD v4.1 (AF = 0)
Sources
BS1 NM_023067.4:c.297_311del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BS1 requires an allele frequency > 0.3% in population databases under generic ACMG, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (AF = 0)
- Absent from gnomAD v4.1 (AF = 0)
Sources
BS2 No data are available regarding the observation of this variant in healthy adults. BS2 requires observation in a healthy adult individual for a recessive, X-linked, or fully penetrant dominant disorder expected to manifest at an early age. Details ▾Hide ▴
Still missing
- No data on observation in healthy adults
BS3 No well-established functional studies demonstrate a neutral or non-deleterious effect for NM_023067.4:c.297_311del. No experimental data characterizing the functional impact of deleting residues Q99-R103 in FOXL2 were identified. Details ▾Hide ▴
Still missing
- No functional studies available to demonstrate neutral effect
BS4 No segregation data are available. BS4 requires lack of cosegregation of the variant with disease in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available
BP2 No data are available on whether NM_023067.4:c.297_311del has been observed in trans with a known pathogenic FOXL2 variant. BP2 requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Still missing
- No data on in trans observation with pathogenic variant
BP3 The deleted region (residues Q99-R103) is not in a repetitive region of FOXL2. The known repetitive elements in FOXL2 include a polyalanine tract at residues 221-234, a poly-glycine tract at approximately residues 57-68, and a poly-proline tract at residues 88-99. Residues Q99-R103 are immediately C-terminal to the poly-proline tract but do not themselves constitute a repetitive region. BP3 is therefore not applicable. Details ▾Hide ▴
Evidence considered
- Deleted residues Q99-R103 are not within any known repetitive region of FOXL2
- Distinct from polyalanine tract (221-234)
- poly-glycine tract (~57-68)
- and poly-proline tract (88-99)
BP4 Multiple lines of computational evidence do not conclusively suggest a benign impact. SpliceAI predicts no splice alteration (max delta 0.00), but this only addresses splicing and does not evaluate the protein-level consequence of a 5-amino-acid in-frame deletion. REVEL and BayesDel are not applicable to indels. Without multiple concordant computational predictions unequivocally supporting a benign interpretation, BP4 cannot be applied. Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.00 (no splice impact only)
- No protein-level in silico predictors available for in-frame deletions
Still missing
- Lack of validated in silico tools to predict pathogenicity of in-frame deletions
Sources
BP5 No data are available regarding observation of this variant in a case with an alternative molecular basis for disease. BP5 requires that the variant be found in an individual with an alternate confirmed molecular cause. Details ▾Hide ▴
Still missing
- No data on alternate molecular diagnosis in carriers
BP6 NM_023067.4:c.297_311del is absent from ClinVar. No reputable source has reported this variant as benign. BP6 requires a reputable source to have classified the variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: absent
- no classification available
Still missing
- No benign classification from any reputable source
Sources
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/APS1 applies when a different nucleotide change is predicted to produce the same amino acid change as an established pathogenic variant. This is an in-frame deletion, not a nucleotide substitution, and there is no alternative nucleotide change that could produce the identical p.(Q99_R103del) protein consequence. Details ▾Hide ▴
No further detail was recorded.
PM5 N/APM5 applies to novel missense variants occurring at the same amino acid residue as a previously established pathogenic missense change. This variant is an in-frame deletion, not a missense substitution. The pm5_candidates assessment confirms ineligibility for classic same-residue PM5 semantics. Details ▾Hide ▴
Sources
pm5_candidates
PP2 N/APP2 applies to missense variants in genes where missense variants are a known mechanism and benign missense variation is rare. This variant is an in-frame deletion, not a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP1 N/ABP1 applies to missense variants in genes where truncating variants are the primary known disease mechanism. This variant is an in-frame deletion, not a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or creation of a new splice site. This variant is an in-frame deletion, not a synonymous substitution. Details ▾Hide ▴
No further detail was recorded.
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 classification framework (PMID:25741868). The standard pathogenic criteria are PVS1, PS1-PS4, PM1-PM6, PP1-PP5. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- FOXL2
- Transcript
- NM_023067.4
- Coding (HGVS c.)
- NM_023067.4:c.297_311del
- Protein (HGVS p.)
- NP_075555.1:p.(Gln99_Arg103del)
- GRCh38
- chr3:138946411 GTGGCGGATGCTATTT>G
- GRCh37
- chr3:138665253 GTGGCGGATGCTATTT>G
Gene diagram
Every interpreted variant in FOXL2, mapped onto the exon structure of NM_023067.4. Select a row to find it on the plot.
FOXL2NM_023067.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in FOXL2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 No computational evidence supports a deleterious effect for this variant. SpliceAI predicts no splice impact (max delta score = 0.00). REVEL and BayesDel are not applicable to insertion-deletion variants. HCI prior scores are not available for FOXL2. Without multiple concordant in silico predictions of deleteriousness, PP3 cannot be applied. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.00 (no splice impact)
- REVEL/BayesDel not available for indels
- HCI prior not available for FOXL2
Still missing
- No in silico protein-level predictors available for in-frame deletions
Sources
BP4 Multiple lines of computational evidence do not conclusively suggest a benign impact. SpliceAI predicts no splice alteration (max delta 0.00), but this only addresses splicing and does not evaluate the protein-level consequence of a 5-amino-acid in-frame deletion. REVEL and BayesDel are not applicable to indels. Without multiple concordant computational predictions unequivocally supporting a benign interpretation, BP4 cannot be applied. Details ▾Hide ▴
Evidence considered
- SpliceAI delta = 0.00 (no splice impact only)
- No protein-level in silico predictors available for in-frame deletions
Still missing
- Lack of validated in silico tools to predict pathogenicity of in-frame deletions
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence or creation of a new splice site. This variant is an in-frame deletion, not a synonymous substitution. Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_023067.4%3Ac.297_311del
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-138665253-GTGGCGGATGCTATTT-…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-138946411-GTGGCGGATGCTAT…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-138946411-GTGGCGGATGCTATTT-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_023067.4%3Ac.297_…
- OncoKB ↗www.oncokb.org/gene/FOXL2/Q99_R103del
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FOXL2+c.297_311del
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.