FOXL2

Final classification

Likely Pathogenic

FOXL2 c.402C>G · p.Cys134Trp

FOXL2

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.

Gene

FOXL2

Transcript

NM_023067.4

HGVS · transcript:coding

NM_023067.4:c.402C>G

Consequence

N/A

GRCh38

chr3:138946321 G>C

GRCh37

chr3:138665163 G>C

Basis 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. ▾

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.

Classification rationale

PS3PM1PM2PP3 Likely Pathogenic

FOXL2 c.402C>G

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 v1.0.¹ 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).² REVEL in silico prediction score of 0.884 supports a deleterious effect on protein function.³ 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.⁴

PS3 + PM1 + PM2 + PP3 → Likely Pathogenic

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 PMID:23372819 ↗

3 revel

4 generic_acmg_combination_rules

Gene diagram · NM_023067.4 · variants mapped to exon structure

FOXL2 NM_023067.4

Fetching transcript structure from UCSC…

Applied criteria · 4 met · select any tile

Met

Not met

Not assessed

N/A

Strength very strong supporting

Pathogenic evidence

PVS

Benign evidence

—

Rationale

Select a criterion.

Sources

Evidence used

Gaps remaining

Rule

—

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

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.

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Hotspot

COSMIC

This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV57725321, n = 901 times).

Hotspots

This variant lies in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

1papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why.

Overexpression of wild-type but not C134W mutant FOXL2 enhances GnRH-induced cell apoptosis by increasing GnRH receptor expression in human granulosa cell tumors.

PMID 23372819 ↗ ONCOKB · functional

Searched

c.402C>GC134W402C>Gp.Cys134Trp

Found

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.

Variant

✓ Names this variant — characterised directly

Applied to

→PM1 supports · met →PS3 supports · met

Why

Variant-specific functional data confirmed loss-of-function effect in somatic context; referenced in PS3 (supporting), PM1, and BS3 assessments.

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 · full text

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots