Analysis in progress
Initialising…
0%
complete
This report is still being assembled — sections appear as each stage finishes. It isn't final yet.
FOXL2
Final classification
VUS
FOXL2 c.297_311del · p.Gln99_Arg103del
FOXL2

NM_023067.4:c.297_311del (p.Gln99_Arg103del) is an in-frame deletion of 15 nucleotides in exon 1 of FOXL2, removing five amino acids (Q99-R103) in a non-repeat region of the gene. Under generic ACMG/AMP 2015, this qualifies for PM4 at moderate strength.

Gene
FOXL2
Transcript
NM_023067.4
HGVS · transcript:coding
NM_023067.4:c.297_311del
Consequence
N/A
GRCh38
chr3:138946411 GTGGCGGATGCTATTT>G
GRCh37
chr3:138665253 GTGGCGGATGCTATTT>G
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: PM2 supporting, PM4 moderate; combination = 1 moderate + 1 supporting, which maps to VUS.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, PM4 moderate; combination = 1 moderate + 1 supporting, which maps to VUS.
Classification rationale
PM2PM4 VUS
FOXL2 c.297_311del

NM_023067.4:c.297_311del (p.Gln99_Arg103del) is an in-frame deletion of 15 nucleotides in exon 1 of FOXL2, removing five amino acids (Q99-R103) in a non-repeat region of the gene. Under generic ACMG/AMP 2015, this qualifies for PM4 at moderate strength. The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, meeting the <0.1% allele frequency threshold for PM2 at supporting level.1 PVS1 is not met: the variant is an in-frame deletion that does not fall into the default null-variant buckets under PMC6185798 (nonsense, frameshift, or canonical splice). The pvs1_variant_assessment confirms generic PVS1 is not applicable.2 No functional studies, de novo data, cosegregation data, case-control data, computational evidence of deleteriousness, or ClinVar classification are available for this variant. Total evidence: 1 moderate (PM4) + 1 supporting (PM2). Under ACMG/AMP 2015 combination rules (PMID:25741868), this is insufficient for likely pathogenic (which requires ≥2 moderate or ≥1 moderate + ≥2 supporting). The variant is classified as a Variant of Uncertain Significance (VUS).3

PM2 + PM4 VUS
2 pvs1_generic_framework ↗pvs1_variant_assessment
3 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 · 2 applied · 20 assessed
Applied · 2
Strength Supporting Moderate Strong Very strong
PM2 supporting Pathogenic
NM_023067.4:c.297_311del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0. Under generic ACMG/AMP 2015, absence from population databases supports pathogenicity at a supporting level (allele frequency < 0.1%).
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (genomes)
PM4 moderate Pathogenic
NM_023067.4:c.297_311del is an in-frame deletion removing 15 nucleotides and 5 amino acids (p.Gln99_Arg103del) in exon 1 of FOXL2. The deletion occurs in a non-repeat region of the gene — it lies upstream of the polyalanine tract at residues 221-234 and is distinct from the poly-glycine (residues ~57-68) and poly-proline (residues 88-99) tracts. In-frame deletions in non-repeat regions that alter protein length are considered moderate evidence of pathogenicity under generic ACMG/AMP 2015.
In-frame deletion of 15 bp removing 5 amino acids (Q99-R103)Confirmed non-repeat region: not within polyalanine (221-234)poly-glycine
Assessed · not applied
Pathogenic
PVS1 NM_023067.4:c.297_311del is an in-frame deletion of 15 nucleotides in exon 1, predicted to remove 5 amino acids (p.Gln99_Arg103del) without disrupting the reading frame.
PS2 No de novo data are available for NM_023067.4:c.297_311del.
PS3 No functional studies have been identified for NM_023067.4:c.297_311del (p.Gln99_Arg103del).
PS4 No case-control or prevalence data are available for this variant.
PM1 The deleted region (residues Q99-R103) lies in the N-terminal region of FOXL2 outside well-characterized functional domains such as the forkhead DNA-binding domain (residues ~151-250).
PM6 No de novo confirmation data are available for this variant.
PP1 No cosegregation data are available for NM_023067.4:c.297_311del.
PP3 No computational evidence supports a deleterious effect for this variant.
PP4 No patient phenotype data are available for comparison to the FOXL2-associated disease spectrum (blepharophimosis, ptosis, epicanthus inversus syndrome / BPES; premature ovarian insufficiency).
PP5 NM_023067.4:c.297_311del is absent from ClinVar with no classification from any submitter, including expert panels.
Benign
BA1 NM_023067.4:c.297_311del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1 NM_023067.4:c.297_311del is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2 No data are available regarding the observation of this variant in healthy adults.
BS3 No well-established functional studies demonstrate a neutral or non-deleterious effect for NM_023067.4:c.297_311del.
BS4 No segregation data are available.
BP2 No data are available on whether NM_023067.4:c.297_311del has been observed in trans with a known pathogenic FOXL2 variant.
BP3 The deleted region (residues Q99-R103) is not in a repetitive region of FOXL2.
BP4 Multiple lines of computational evidence do not conclusively suggest a benign impact.
BP5 No data are available regarding observation of this variant in a case with an alternative molecular basis for disease.
BP6 NM_023067.4:c.297_311del is absent from ClinVar.
N/A · 5 PS1 · PM5 · PP2 · BP1 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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.
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
Functional / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
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.
Sources & reference links
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots