About FOXL2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FOXL2 c.469C>G, p.(Pro157Ala)
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: 1
Pathogenic criteria applied · 2
PM1Supporting
PM1 · supporting
Located at codon 157 within the forkhead DNA-binding domain of FOXL2 (approximately residues 152–256), a critical and well-established functional domain required for transcription factor activity. Population data show extreme constraint (gnomAD AF ~5e-06), consistent with absence of benign variation in this domain. Residue-specific hotspot not identified at cancerhotspots.org, but domain-level application is supported.
PM2Supporting
PM2 · supporting
Extremely low allele frequency in population databases, well below the 0.1% PM2 threshold. gnomAD v2.1: 1/203,794 alleles (AF=4.9e-06); gnomAD v4.1: 9/1,589,638 alleles (AF=5.66e-06); absent from gnomAD-Canada v1.0. No homozygotes observed.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no significant impact. REVEL score 0.291 (below 0.5 pathogenic threshold), BayesDel score -0.188 (predicted benign), and SpliceAI max delta 0.00 (no splicing impact). HCI prior not available.
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: PM1 supporting, PM2 supporting, BP4 supporting benign; combination = 2 supporting + 1 supporting benign, 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
9 / 1,589,638 alleles
gnomAD v4.1: 9 / 1,589,638 alleles. Recorded AF 5.66167e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.90692e-06; MAF= 0.00049%, 1/203794 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.14563e-05; MAF= 0.00115%, 1/87288 alleles, homozygotes = 0).
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 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
6 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV57730775, n = 6 times).
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.
29 criteria with recorded statuses: 3 met · 20 not met · 1 not assessed · 5 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.469C>G (p.Pro157Ala) is a missense variant in the forkhead DNA-binding domain of FOXL2.
This variant is extremely rare in population databases (gnomAD v2.1: 1/203,794 alleles, AF=4.9e-06; v4.1: 9/1,589,638 alleles, AF=5.66e-06), meeting PM2 at supporting strength.
Pro157 resides within the forkhead domain, a critical and well-established functional domain required for FOXL2 DNA-binding and transcriptional activity, meeting PM1 at supporting strength.
Multiple computational predictors do not support a deleterious effect: REVEL score 0.291 (below pathogenic threshold), BayesDel score -0.188 (predicted benign), and SpliceAI max delta 0.00, meeting BP4 at supporting benign strength.
This variant has been observed in somatic cancers (COSMIC: n=6) but lacks germline pathogenicity evidence. It is absent from ClinVar and no publications have directly characterized p.Pro157Ala.
The evidence profile includes two pathogenic supporting criteria (PM1, PM2) and one benign supporting criterion (BP4), resulting in an indeterminate classification (Variant of Uncertain Significance) under the generic ACMG/AMP 2015 framework.
No criteria match.
Met · 3
PM1 SupportingLocated at codon 157 within the forkhead DNA-binding domain of FOXL2 (approximately residues 152–256), a critical and well-established functional domain required for transcription factor activity. Population data show extreme constraint (gnomAD AF ~5e-06), consistent with absence of benign variation in this domain. Residue-specific hotspot not identified at cancerhotspots.org, but domain-level application is supported. Details ▾Hide ▴
Evidence considered
- FOXL2 forkhead domain is a well-characterized functional domain critical for DNA binding and transcriptional regulation
- Pro157 is positioned at the N-terminal region of the forkhead domain
- gnomAD extreme constraint: v2.1 AF=4.9e-06
- v4.1 AF=5.66e-06
- supporting absence of benign variation
- cancerhotspots.org: no residue-specific hotspot identified
Still missing
- Exact forkhead domain boundary assignment relative to Pro157 may vary across annotation sources
- No residue-specific functional data for Pro157 within the domain
Sources
PM2 SupportingExtremely low allele frequency in population databases, well below the 0.1% PM2 threshold. gnomAD v2.1: 1/203,794 alleles (AF=4.9e-06); gnomAD v4.1: 9/1,589,638 alleles (AF=5.66e-06); absent from gnomAD-Canada v1.0. No homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=4.9e-06
- 1/203
- 794 alleles
- 0 homozygotes
- gnomAD v4.1: AF=5.66e-06
- 9/1
- 589
- 638 alleles
- grpmax FAF=1.417e-05
- gnomAD-Canada v1.0: absent
Sources
BP4 SupportingMultiple lines of computational evidence suggest no significant impact. REVEL score 0.291 (below 0.5 pathogenic threshold), BayesDel score -0.188 (predicted benign), and SpliceAI max delta 0.00 (no splicing impact). HCI prior not available. Details ▾Hide ▴
Evidence considered
- REVEL: 0.291 (below 0.5 threshold)
- BayesDel: -0.188 (negative
- predicts benign)
- SpliceAI: max delta 0.00 (no splice alteration)
- HCI prior: not available for FOXL2
Sources
Not met · 20 · evaluated, threshold not reached
PS1 No previously established pathogenic variant at this amino acid position (Pro157) has been identified in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entries for NM_023067.4:c.469C>G or any variant at codon 157
Still missing
- No curated pathogenic variant database entries at Pro157
Sources
PS2 No de novo occurrence data available for this variant. No parental testing or trio sequencing results in the case record or literature. Details ▾Hide ▴
Still missing
- No de novo status assessment available
PS3 No variant-specific functional studies identified. OncoKB reports Unknown Oncogenic Effect with no curated functional evidence. Literature search returned no publications evaluating the functional impact of p.Pro157Ala. COSMIC somatic occurrence (n=6) does not constitute functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional data
- COSMIC: COSV57730775
- somatic count 6 — no functional characterization
- Literature screen: no PMIDs with functional data for this variant
Still missing
- No experimental functional characterization of p.Pro157Ala exists
Sources
PS4 No case-control or prevalence data comparing affected individuals to controls for this variant is available. Details ▾Hide ▴
Still missing
- No case-control studies or cohort enrichment data
PM5 No pathogenic missense variant at the same codon (Pro157) identified in ClinVar or literature. PM5 candidate harvesting returned no eligible comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search returned 0 same-residue candidates in ClinVar
- ClinVar has no entries for any variant at codon 157
Sources
pm5_candidatesclinvar ↗
PM6 No de novo status confirmed for this variant. No trio data or de novo reports available. Details ▾Hide ▴
Still missing
- No de novo data available
PP1 No co-segregation data available for this variant. No family studies identified. Details ▾Hide ▴
Still missing
- No segregation data
PP3 Multiple computational predictors do not support a deleterious effect. REVEL score 0.291 (below typical pathogenic threshold of 0.5). BayesDel score -0.188 (negative, predicting benign). SpliceAI max delta 0.00 (no splicing impact). No HCI prior score available for FOXL2. Details ▾Hide ▴
Evidence considered
- REVEL: 0.291
- BayesDel: -0.188
- SpliceAI: max delta 0.00
- HCI prior: not available for FOXL2
Sources
PP4 No patient phenotype or family history data available in the case record to evaluate phenotype specificity for FOXL2-related disorders. Details ▾Hide ▴
Still missing
- No patient phenotype data provided
PP5 This variant is absent from ClinVar; no reputable source has classified it as pathogenic. Details ▾Hide ▴
BA1 gnomAD allele frequency is far below the 1% BA1 threshold. v2.1 AF=4.9e-06, v4.1 AF=5.66e-06. Details ▾Hide ▴
Evidence considered
- Maximum observed AF: 5.34e-05 (gnomAD v4.1 AMR subpopulation)
Sources
BS1 gnomAD allele frequency is far below the 0.3% BS1 threshold. v2.1 AF=4.9e-06, v4.1 AF=5.66e-06. Details ▾Hide ▴
Evidence considered
- Maximum observed AF: 5.34e-05 (gnomAD v4.1 AMR subpopulation)
Sources
BS2 No evidence of this variant being observed in healthy adults with complete penetrance for a dominant disorder. gnomAD carriers lack phenotype annotation. Details ▾Hide ▴
Still missing
- No phenotype data for gnomAD carriers
BS3 No well-established functional studies demonstrating no damaging effect for this variant. No functional data available in OncoKB or the literature. Details ▾Hide ▴
Still missing
- No functional characterization of p.Pro157Ala
BS4 No segregation data available to evaluate lack of segregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data
BP1 FOXL2-related disease (BPES, POI) is known to be caused by missense variants; this is not a gene where only truncating variants cause disease. Details ▾Hide ▴
Evidence considered
- Over 100 germline missense variants in FOXL2 are associated with BPES (PMID:34727551)
BP2 No evidence of this variant observed in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for a recessive disorder. Details ▾Hide ▴
Still missing
- No phase data available
BP5 No alternate molecular basis for disease has been identified in the case record. Details ▾Hide ▴
Still missing
- No alternate genetic cause evaluated
BP6 This variant is absent from ClinVar; no reputable source has classified it as benign. Details ▾Hide ▴
PS5 No well-established, validated functional assay demonstrating a pathogenic effect for this variant is available in a clinical diagnostic setting. Details ▾Hide ▴
Still missing
- No reproducible clinical-grade functional assay exists for FOXL2 missense variants at this position
Not assessed · 1 · no assessment recorded
PP2 FOXL2 missense variants are a known mechanism for blepharophimosis, ptosis, and epicanthus inversus syndrome (BPES) and premature ovarian insufficiency. However, gene-level missense constraint metrics (e.g., Z-score, gnomAD missense o/e) were not retrieved. Cannot definitively apply PP2 without quantitative constraint data. Details ▾Hide ▴
Evidence considered
- FOXL2 is associated with BPES and POI through germline missense variants
- gnomAD shows extreme overall constraint but gene-level missense constraint metrics not available in the evidence record
Still missing
- Need gnomAD missense Z-score or o/e constraint metric for FOXL2
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Pro157Ala); does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). Not eligible for PVS1 under ClinGen SVI PVS1 decision tree (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution at codon 157 (Pro→Ala)
- not predicted to cause nonsense-mediated decay or abolish canonical splicing
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/ASkipped: FOXL2-related disorders are autosomal dominant; PM3 is for recessive disorders. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped: variant is a substitution, not a protein-length-altering change (indel/stop-loss). Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASkipped: variant is a substitution, not an in-frame indel in a non-repetitive region. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AMissense variant (c.469C>G, p.Pro157Ala), not synonymous or intronic. BP7 is reserved for synonymous variants without splice impact. Details ▾Hide ▴
Identifiers
- Gene
- FOXL2
- Transcript
- NM_023067.4
- Coding (HGVS c.)
- NM_023067.4:c.469C>G
- Protein (HGVS p.)
- NP_075555.1:p.(Pro157Ala)
- GRCh38
- chr3:138946254 G>C
- GRCh37
- chr3:138665096 G>C
- COSMIC
- COSV57730775
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
9 / 1,589,638 alleles
AF 5.66e-06 · 0 homozygotes · FAF 1.42e-05
gnomAD v2.1
1 / 203,794 alleles
AF 4.91e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 5.7e-06 · 9 / 1,589,638 alleles · 0 hom · FAF 1.4e-05
| Admixed American3 / 56,168 | 5.3e-05 |
| African/African American2 / 74,216 | 2.7e-05 |
| Remaining individuals1 / 61,518 | 1.6e-05 |
| European (non-Finnish)3 / 1,169,148 | 2.6e-06 |
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 4.9e-06 · 1 / 203,794 alleles · 0 hom
| European (non-Finnish)1 / 87,288 | 1.1e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 5.66167e-06; MAF= 0.00057%, 9/1589638 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.34112e-05; MAF= 0.00534%, 3/56168 alleles, homozygotes = 0); grpmax FAF= 1.417e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.90692e-06; MAF= 0.00049%, 1/203794 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.14563e-05; MAF= 0.00115%, 1/87288 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.291
- BayesDel
- -0.188
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no significant impact. REVEL score 0.291 (below 0.5 pathogenic threshold), BayesDel score -0.188 (predicted benign), and SpliceAI max delta 0.00 (no splicing impact). HCI prior not available. Details ▾Hide ▴
Evidence considered
- REVEL: 0.291 (below 0.5 threshold)
- BayesDel: -0.188 (negative
- predicts benign)
- SpliceAI: max delta 0.00 (no splice alteration)
- HCI prior: not available for FOXL2
Sources
PP3 Multiple computational predictors do not support a deleterious effect. REVEL score 0.291 (below typical pathogenic threshold of 0.5). BayesDel score -0.188 (negative, predicting benign). SpliceAI max delta 0.00 (no splicing impact). No HCI prior score available for FOXL2. Details ▾Hide ▴
Evidence considered
- REVEL: 0.291
- BayesDel: -0.188
- SpliceAI: max delta 0.00
- HCI prior: not available for FOXL2
Sources
BP7 N/AMissense variant (c.469C>G, p.Pro157Ala), not synonymous or intronic. BP7 is reserved for synonymous variants without splice impact. Details ▾Hide ▴
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.291. BayesDel score = -0.188397.
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
9 / 1,589,638 recorded alleles
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.469C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-138665096-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-138946254-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-138946254-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_023067.4%3Ac.469C…
- OncoKB ↗www.oncokb.org/gene/FOXL2/P157A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=131483134
- 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
This variant is present in gnomAD v4.1 (AF= 5.66167e-06; MAF= 0.00057%, 9/1589638 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 5.34112e-05; MAF= 0.00534%, 3/56168 alleles, homozygotes = 0); grpmax FAF= 1.417e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 4.90692e-06; MAF= 0.00049%, 1/203794 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.14563e-05; MAF= 0.00115%, 1/87288 alleles, homozygotes = 0).
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 = 0.291. BayesDel score = -0.188397.
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 previously been reported in somatic cancers (COSMIC; COSV57730775, n = 6 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.