NM_023067.4:c.386C>T

FOXL2 · NP_075555.1:p.(Thr129Met) · NM_023067.4

GRCh37: chr3:138665179 G>A · GRCh38: chr3:138946337 G>A

Gene: FOXL2 Transcript: NM_023067.4

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

FOXL2

Transcript

NM_023067.4

Protein

NP_075555.1:p.(Thr129Met)

gnomAD AF

6.195894352566215e-07 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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).

Final determination: Under generic ACMG/AMP 2015 (PMID 25741868) fallback combination rules, the adjudicated criteria PM2 (supporting) + PP3 (supporting) = 2 supporting criteria meet no Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	Not applicable: c.386C>T is a missense substitution, so no null-variant mechanism (e.g., nonsense-mediated decay) is triggered.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no prior report establishes p.Thr129Met as pathogenic; the variant is absent from ClinVar and the literature.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no proband genotype or confirmed-parentage data exist to establish a de novo occurrence.	clinvar generic_acmg_combination_rules
PS3	Not assessed	Not assessed: no variant-specific functional assay evidence exists for p.Thr129Met in any source.	generic_acmg_combination_rules oncokb clinvar spliceai
PS4	Not assessed	Not assessed: no case-control or cohort data on this variant exist, so enrichment cannot be evaluated.
PM1	Not assessed	Not assessed: no statistically significant hotspot and no documented domain annotation for residue 129 are available.	oncokb pvs1_gene_context
PM2	Met	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 gnomad_v2 gnomad_canada clinvar generic_acmg_combination_rules
PM3	N/A	Not applicable: PM3 applies only to recessive disorders, and FOXL2-associated disease is autosomal dominant.	pvs1_gene_context clinvar generic_acmg_combination_rules
PM4	N/A	Not applicable: missense substitution causes no protein length change, so the stop-loss/in-frame indel criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no pathogenic missense at residue 129 other than p.Thr129Met has been reported.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no de novo evidence of any kind exists for this variant.	clinvar generic_acmg_combination_rules
PP1	Not assessed	Not assessed: no pedigree or segregation data exist for this variant.	clinvar generic_acmg_combination_rules
PP2	Not assessed	Not assessed: no gene-level missense constraint metrics (e.g., gnomAD Z-score) are available.	pvs1_gene_context
PP3	Met	Met (supporting): REVEL 0.822 falls within the ClinGen-calibrated PP3 supporting band (0.773-0.931).	revel spliceai bayesdel generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no phenotype data exist for any carrier of c.386C>T.	oncokb
PP5	Not met	Not met: the variant has no ClinVar record, so no expert-panel Pathogenic classification exists to trigger PP5.	clinvar
BA1	Not met	Not met: highest allele frequency (0.00008%, NFE) is orders of magnitude below the >1% BA1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
BS1	Not met	Not met: highest allele frequency (0.00008%) is far below the >0.3% BS1 threshold.	gnomad_v4 gnomad_v2 gnomad_canada generic_acmg_combination_rules
BS2	Not met	Not met: only one heterozygous reference allele (0 homozygotes) exists, with no phenotype confirmation of an unaffected adult.	gnomad_v4 gnomad_v2 gnomad_canada clinvar generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional studies demonstrating no damaging effect are available.	generic_acmg_combination_rules spliceai oncokb clinvar
BS4	Not assessed	Not assessed: no family testing data exist to demonstrate non-segregation.	clinvar gnomad_v4 generic_acmg_combination_rules
BP1	Not met	Not met: missense variants are an established FOXL2 disease mechanism, so the truncation-only premise fails.	oncokb pvs1_gene_context
BP2	Not met	Not met: no pathogenic variant was observed in trans or cis with c.386C>T.	clinvar gnomad_v4 generic_acmg_combination_rules
BP3	N/A	Not applicable: missense substitution does not alter protein length within a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.822 predicts a damaging effect, contradicting the multiple no-impact lines BP4 requires.	spliceai revel bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband data identifying an alternative molecular basis are available.
BP6	Not met	Not met: the variant has no ClinVar record, so no expert-panel Benign classification exists to trigger BP6.	clinvar
BP7	N/A	Not applicable: the variant is missense, not synonymous, so the silent-variant criterion does not apply.	generic_acmg_combination_rules

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