Classification rationale

PM2PP3 VUS

FOXL2 c.386C>T

PM2 (Supporting): variant is absent from gnomAD v2.1 and ClinVar, with gnomAD v4.1 frequency 6.2e-07 (1/1,613,972 alleles), about 1,000-fold below the <0.1% threshold. PP3 (Supporting): REVEL 0.822 falls within the ClinGen-calibrated supporting band (0.773-0.931). Two supporting criteria meet no ACMG/AMP 2015 pathogenic or benign combination, so the variant is classified as Variant of Uncertain Significance (VUS).

PM2 + PP3 → VUS

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

FOXL2 NM_023067.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): gnomAD v4.1 frequency 6.2e-07 (1/1,613,972 alleles) is ~1,000-fold below the <0.1% threshold.

gnomAD v4.1: total AF 6.1959e-07 (1/1,613,972 alleles), exome AF 6.8413e-07 (1/1,461,704), 0 homozygotes; highest subpopulation NFE AF 8.4748e-07 (gnomad_v4)gnomAD v2.1: absent (gnomad_v2)gnomAD-Canada v1.0: absent (gnomad_canada)

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗clinvar ↗

✓

PP3 supporting Pathogenic

Met (supporting): REVEL 0.822 falls within the ClinGen-calibrated PP3 supporting band (0.773-0.931).

REVEL score 0.822 for NM_023067.4:c.386C>T (p.Thr129Met); ClinGen SVI-calibrated PP3 supporting threshold REVEL >= 0.773 from Pejaver et al., Am J Hum Genet 2022;109(12):2163-2177 (PMID 36413997); 0.822 is within the supporting band (0.773-0.931) and below the PP3 strong threshold of 0.932.SpliceAI max delta score 0.00 (DS_AG 0.0, DS_AL 0.0, DS_DG 0.0, DS_DL 0.0; variant consequence sequence_variant) for NM_023067.4:c.386C>T; scores below ~0.2 indicate minimal probability of splice alteration (Jaganathan et al., Nat Genet 2019;51(8):1289-1301, PMID 30661751); splice sub-path negative and does not support PP3.BayesDel score 0.221987 retrieved from local lookup but excluded: no verified published threshold is available to this pipeline, so the score is treated as insufficiently calibrated for PP3 (and BP4).

spliceai ↗

Assessed · not applied

Pathogenic

PS1 Not met: no prior report establishes p.Thr129Met as pathogenic; the variant is absent from ClinVar and the literature.

PS2 Not assessed: no proband genotype or confirmed-parentage data exist to establish a de novo occurrence.

PS3 Not assessed: no variant-specific functional assay evidence exists for p.Thr129Met in any source.

PS4 Not assessed: no case-control or cohort data on this variant exist, so enrichment cannot be evaluated.

PM1 Not assessed: no statistically significant hotspot and no documented domain annotation for residue 129 are available.

PM5 Not assessed: no pathogenic missense at residue 129 other than p.Thr129Met has been reported.

PM6 Not assessed: no de novo evidence of any kind exists for this variant.

PP1 Not assessed: no pedigree or segregation data exist for this variant.

PP2 Not assessed: no gene-level missense constraint metrics (e.g., gnomAD Z-score) are available.

PP4 Not assessed: no phenotype data exist for any carrier of c.386C>T.

PP5 Not met: the variant has no ClinVar record, so no expert-panel Pathogenic classification exists to trigger PP5.

Benign

BA1 Not met: highest allele frequency (0.00008%, NFE) is orders of magnitude below the >1% BA1 threshold.

BS1 Not met: highest allele frequency (0.00008%) is far below the >0.3% BS1 threshold.

BS2 Not met: only one heterozygous reference allele (0 homozygotes) exists, with no phenotype confirmation of an unaffected adult.

BS3 Not assessed: no functional studies demonstrating no damaging effect are available.

BS4 Not assessed: no family testing data exist to demonstrate non-segregation.

BP1 Not met: missense variants are an established FOXL2 disease mechanism, so the truncation-only premise fails.

BP2 Not met: no pathogenic variant was observed in trans or cis with c.386C>T.

BP4 Not met: REVEL 0.822 predicts a damaging effect, contradicting the multiple no-impact lines BP4 requires.

BP5 Not assessed: no proband data identifying an alternative molecular basis are available.

BP6 Not met: the variant has no ClinVar record, so no expert-panel Benign classification exists to trigger BP6.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

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).

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

6.2e-05% · 1 / 1,613,972
0 hom

European (non-Finnish)

1 / 1,179,968

8.5e-05%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

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 = 0.822. BayesDel score = 0.221987.

SpliceAI ↗

Functional Unknown Oncogenic Effect

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.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots