About FOXL2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FOXL2 c.402C>G, p.(Cys134Trp)
Classification
Likely pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
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: 4
Benign evidence criteria: 0
Pathogenic criteria applied · 4
PS3Supporting
PS3 · supporting
Functional studies in KGN granulosa cell tumor cells (PMID:23372819) demonstrate that wild-type FOXL2 upregulates GnRH receptor expression and enhances GnRH-induced apoptosis, whereas C134W mutant FOXL2 does not, consistent with a loss-of-function effect. This is a single well-controlled in vitro study in a somatic cell context; applied at supporting strength for germline interpretation.
PM1Moderate
PM1 · moderate
The p.Cys134Trp alteration lies within the forkhead DNA-binding domain wing 2 region, a statistically significant mutational hotspot (cancerhotspots.org) with 901 somatic occurrences in COSMIC (COSV57725321). The C134 residue is critical for FOXL2 protein-protein interactions and transcriptional regulatory function.
PM2Moderate
PM2 · moderate
This variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0.0%). This absence from large population cohorts is consistent with a rare pathogenic variant.
PP3Supporting
PP3 · supporting
REVEL score of 0.884 predicts a deleterious effect on protein function. BayesDel score of 0.353 is below typical pathogenicity thresholds, and SpliceAI delta score is 0.00 (no splicing impact). The high REVEL score provides one line of in silico evidence supporting a deleterious effect.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Likely pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 supporting, PM1 moderate, PM2 moderate, PP3 supporting; combination = 2 moderate + 2 supporting, which maps to Likely Pathogenic.
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.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
901 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57725321, n = 901 times).
Cancer Hotspots
This variant lies 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.
29 criteria with recorded statuses: 4 met · 16 not met · 2 not assessed · 7 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.402C>G (p.Cys134Trp) in FOXL2 is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0.
The variant alters codon 134 in the forkhead DNA-binding domain wing 2 region, a statistically significant mutational hotspot with 901 somatic occurrences in COSMIC (COSV57725321).
Functional studies in KGN granulosa cell tumor cells demonstrate that C134W mutant FOXL2 fails to upregulate GnRH receptor expression and fails to enhance GnRH-induced apoptosis, whereas wild-type FOXL2 performs both functions, consistent with a loss-of-function effect (PMID:23372819).
REVEL in silico prediction score of 0.884 supports a deleterious effect on protein function.
Applying generic ACMG/AMP 2015 final classification combination rules (PMID:25741868): two moderate criteria (PM1, PM2) and two supporting criteria (PS3, PP3) are met, consistent with a Likely Pathogenic classification.
No criteria match.
Met · 4
PS3 SupportingFunctional studies in KGN granulosa cell tumor cells (PMID:23372819) demonstrate that wild-type FOXL2 upregulates GnRH receptor expression and enhances GnRH-induced apoptosis, whereas C134W mutant FOXL2 does not, consistent with a loss-of-function effect. This is a single well-controlled in vitro study in a somatic cell context; applied at supporting strength for germline interpretation. Details ▾Hide ▴
Evidence considered
- Overexpression of wild-type FOXL2 increased GnRHR mRNA and protein levels
- C134W mutant did not.
- Wild-type FOXL2 enhanced GnRH-induced apoptosis (MTT assay
- cleaved caspase-3)
- siRNA knockdown of FOXL2 reduced GnRHR in normal granulosa cells but not in heterozygous mutant KGN cells
- consistent with altered function of the mutant.
Still missing
- Functional data are from a somatic cancer cell line (KGN)
- not from germline-relevant tissue or model.
Sources
PM1 ModerateThe p.Cys134Trp alteration lies within the forkhead DNA-binding domain wing 2 region, a statistically significant mutational hotspot (cancerhotspots.org) with 901 somatic occurrences in COSMIC (COSV57725321). The C134 residue is critical for FOXL2 protein-protein interactions and transcriptional regulatory function. Details ▾Hide ▴
Evidence considered
- Located in forkhead DNA-binding domain wing 2 region (residue 134).
- Statistically significant hotspot per cancerhotspots.org.
- COSMIC COSV57725321 with 901 somatic occurrences across adult granulosa cell tumors.
- C134W mutation disrupts FOXL2-mediated transcriptional regulation of GnRHR (PMID:23372819).
Still missing
- Hotspot designation is derived from somatic cancer data rather than germline variation.
Sources
PM2 ModerateThis variant is absent from all population databases: gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 (allele frequency 0.0%). This absence from large population cohorts is consistent with a rare pathogenic variant. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes).
- Absent from gnomAD-Canada v1.0 (HostSeq genomes).
Sources
PP3 SupportingREVEL score of 0.884 predicts a deleterious effect on protein function. BayesDel score of 0.353 is below typical pathogenicity thresholds, and SpliceAI delta score is 0.00 (no splicing impact). The high REVEL score provides one line of in silico evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.884 (deleterious prediction).
- BayesDel score: 0.353 (below typical pathogenicity threshold).
- SpliceAI max delta: 0.00 (no splicing impact predicted).
Still missing
- Discordant in silico predictions: REVEL supports deleterious effect
- BayesDel does not reach typical pathogenic threshold.
Sources
Not met · 16 · evaluated, threshold not reached
PS2 No de novo observation of NM_023067.4:c.402C>G with confirmed paternity and maternity was identified in any reviewed publication. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No trio or de novo sequencing data available for this variant.
PS4 No case-control data comparing variant prevalence in germline-affected individuals versus unaffected controls is available. The variant is a known somatic driver in ~97% of adult granulosa cell tumors, but this does not constitute germline case-control evidence. Details ▾Hide ▴
Evidence considered
- No germline case-control data available
- somatic prevalence in GCT does not satisfy PS4.
Still missing
- No cohort or case-control studies of germline FOXL2 c.402C>G.
PM6 No de novo observation of this variant has been reported, with or without confirmation of paternity and maternity. Details ▾Hide ▴
Evidence considered
- No de novo data available.
Still missing
- No de novo sequencing or trio data for this variant.
PP1 No co-segregation data is available for this variant in any family. Details ▾Hide ▴
Evidence considered
- No co-segregation data available.
Still missing
- No family studies or segregation analysis available.
PP4 No patient phenotype or clinical data were provided for this assessment. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No clinical phenotype or family history data available.
Still missing
- Patient phenotype and clinical context not provided.
BA1 This variant is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada v1.0; allele frequency 0.0%). Does not meet the BA1 threshold of >1% allele frequency. Details ▾Hide ▴
Evidence considered
- Allele frequency is 0.0% in all population databases.
Sources
BS1 This variant is absent from population databases (allele frequency 0.0%). Does not meet the BS1 threshold of >0.3% allele frequency. Details ▾Hide ▴
Evidence considered
- Allele frequency is 0.0% in all population databases.
Sources
BS2 No observation of this variant in a healthy adult individual has been reported for a disorder expected to be fully penetrant. The variant is absent from population databases altogether. Details ▾Hide ▴
Evidence considered
- No observation in healthy adults reported.
BS3 The available functional study (PMID:23372819) demonstrates a damaging effect for the C134W mutant (loss of GnRHR upregulation and failure to enhance GnRH-induced apoptosis), which is inconsistent with a benign functional assessment. Details ▾Hide ▴
BS4 No segregation data is available to assess lack of co-segregation with disease. Details ▾Hide ▴
Evidence considered
- No segregation data available.
BP1 FOXL2 is associated with blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) via both truncating and missense germline variants, with over 100 germline variants described. Missense variants are a well-established pathogenic mechanism in this gene, so BP1 does not apply. Details ▾Hide ▴
Evidence considered
- FOXL2 has both truncating and missense pathogenic germline variants.
- Over 100 germline FOXL2 variants are associated with BPES
- including missense variants.
BP2 No observation of this variant in trans with a fully penetrant dominant pathogenic variant has been reported. Details ▾Hide ▴
Evidence considered
- No trans configuration data available.
BP4 REVEL score of 0.884 predicts a deleterious effect, contradicting the BP4 requirement that multiple lines of computational evidence suggest no impact. BayesDel (0.353) is inconclusive, and SpliceAI (0.00) shows no splicing effect, but the high REVEL score precludes application of BP4. Details ▾Hide ▴
Evidence considered
- REVEL 0.884 contradicts benign prediction.
- Computational evidence does not uniformly suggest no impact.
Sources
BP5 No observation of this variant in a case with an alternate molecular cause for disease has been reported. Details ▾Hide ▴
Evidence considered
- No alternate molecular cause data available.
BP6 No reputable source reports this variant as benign. The variant is absent from ClinVar and no clinical laboratory has classified it as benign. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no benign classification from any source.
PS5 No data on trans configuration with a known pathogenic variant. FOXL2-associated disorders (BPES) are autosomal dominant, and no second pathogenic variant was identified. Details ▾Hide ▴
Evidence considered
- No trans data
- FOXL2 disorders are dominant.
Not assessed · 2 · no assessment recorded
PP2 HCI prior score is not available for FOXL2, and a formal assessment of the gene's rate of benign missense variation versus pathogenic missense variation cannot be made per the generic ACMG/AMP framework without this data. Details ▾Hide ▴
Evidence considered
- HCI prior not found for FOXL2.
Still missing
- HCI prior scores not available for FOXL2.
PP5 No reputable source (e.g., clinical diagnostic laboratory) has reported this variant as pathogenic with evidence that is unavailable for independent review. OncoKB classification of Likely Oncogenic is a somatic cancer annotation and does not satisfy PP5 for germline interpretation. Details ▾Hide ▴
Evidence considered
- No germline clinical classification available from a reputable source.
Still missing
- No clinical laboratory report or database entry reports this variant as germline pathogenic.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (p.Cys134Trp). It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant type is missense
- not a null variant eligible for PVS1.
Sources
PS1 N/AOnly one nucleotide substitution (c.402C>G, TGT→TGG) can produce the p.Cys134Trp amino acid change at codon 134. No alternative nucleotide change at this codon yields the same amino acid, precluding a PS1 comparison. Details ▾Hide ▴
Evidence considered
- TGT→TGG is the sole nucleotide change producing C134W.
PM3 N/APM3 applies to recessive disorders where a pathogenic variant is detected in trans; FOXL2-associated disorders (BPES) are autosomal dominant. Details ▾Hide ▴
Evidence considered
- FOXL2 disorders are autosomal dominant
- PM3 is for recessive conditions.
PM4 N/APM4 applies to protein length changes from in-frame indels or stop-loss variants; not applicable to a single-nucleotide missense substitution. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not an in-frame indel or stop-loss.
PM5 N/ANo same-residue missense comparator variants with established pathogenicity were identified; automatic PM5 candidate harvesting could not confirm classic PM5 semantics for this residue. Details ▾Hide ▴
Evidence considered
- No comparator missense variants at residue 134 with established pathogenicity found.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions; not applicable to a single-nucleotide substitution. Details ▾Hide ▴
Evidence considered
- Variant is a substitution
- not an in-frame indel.
BP7 N/AThis is a missense variant (c.402C>G, p.Cys134Trp). BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Identifiers
- Gene
- FOXL2
- Transcript
- NM_023067.4
- Coding (HGVS c.)
- NM_023067.4:c.402C>G
- Protein (HGVS p.)
- NP_075555.1:p.(Cys134Trp)
- GRCh38
- chr3:138946321 G>C
- GRCh37
- chr3:138665163 G>C
- COSMIC
- COSV57725321
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
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in FOXL2
—
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
- 0.884
- BayesDel
- 0.353
How the predictions were used
PP3 SupportingREVEL score of 0.884 predicts a deleterious effect on protein function. BayesDel score of 0.353 is below typical pathogenicity thresholds, and SpliceAI delta score is 0.00 (no splicing impact). The high REVEL score provides one line of in silico evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL score: 0.884 (deleterious prediction).
- BayesDel score: 0.353 (below typical pathogenicity threshold).
- SpliceAI max delta: 0.00 (no splicing impact predicted).
Still missing
- Discordant in silico predictions: REVEL supports deleterious effect
- BayesDel does not reach typical pathogenic threshold.
Sources
BP4 REVEL score of 0.884 predicts a deleterious effect, contradicting the BP4 requirement that multiple lines of computational evidence suggest no impact. BayesDel (0.353) is inconclusive, and SpliceAI (0.00) shows no splicing effect, but the high REVEL score precludes application of BP4. Details ▾Hide ▴
Evidence considered
- REVEL 0.884 contradicts benign prediction.
- Computational evidence does not uniformly suggest no impact.
Sources
BP7 N/AThis is a missense variant (c.402C>G, p.Cys134Trp). BP7 applies only to synonymous variants with no predicted splicing impact. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.884. BayesDel score = 0.353418.
1 paper record listed. 1 cited in the classification.
Cited in the classification
-
PMID 23372819 ↗Overexpression of wild-type but not C134W mutant FOXL2 enhances GnRH-induced cell apoptosis by increasing GnRH receptor expression in human granulosa cell tumors.C134W mutant FOXL2 (c.402C>G) fails to upregulate GnRH receptor mRNA and protein expression in human KGN granulosa cell tumor cells, whereas wild-type FOXL2 increases GnRHR levels and enhances GnRH-induced apoptosis. siRNA knockdown of FOXL2 reduces GnRHR in normal granulosa cells but not in heterozygous mutant KGN cells, indicating the C134W mutation impairs FOXL2-mediated transcriptional regulation of GnRHR.→ PS3 → PM1 Names this variant
Source detail
Overexpression of wild-type FOXL2 increases both mRNA and protein levels of GnRH receptor and consequently enhances GnRH-induced apoptosis. Importantly, neither the expression levels of GnRH receptor nor GnRH-induced apoptosis were affected by overexpression of the C134W mutant FOXL2.
Location Abstract; Results paragraphs 1-5; Figures 3, 4, 5; Discussion paragraphs 1-5
Context KGN human granulosa cell tumor-derived cell line (heterozygous FOXL2 c.402C>G); immortalized human granulosa-luteal cells (wild-type FOXL2); Western blot, RT-qPCR, MTT assay, cleaved caspase-3 detection
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.402C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-138665163-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-138946321-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-138946321-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_023067.4%3Ac.402C…
- OncoKB ↗www.oncokb.org/gene/FOXL2/C134W
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=131482698
- 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). REVEL score = 0.884. BayesDel score = 0.353418.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57725321, n = 901 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.