PM2 (moderate): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, supporting a rare variant not observed in the general population.1 BP4 (supporting benign): Multiple computational predictors (REVEL 0.377, BayesDel -0.0395, SpliceAI 0.00) suggest no significant impact on the gene product or splicing.2 PVS1, PS1, PS2, PS3, PS4, PS5, PM1, PM5, PM6, PP1, PP3, PP4, PP5, BA1, BS1, BS2, BS3, BS4, BP2, BP5, BP6 are not met. BP1, BP7, BP3, PM3, PM4 are not applicable. PP2 is not assessed due to absent gnomAD constraint metrics. Classification: Uncertain Significance (VUS). One moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) do not meet thresholds for Likely Pathogenic (requires ≥2 moderate or ≥1 strong) or Likely Benign (requires ≥2 supporting benign).3
FGFR2
Final classification
VUS
FGFR2 c.1223A>C · p.Asp408Ala
FGFR2
PM2 (moderate): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, supporting a rare variant not observed in the general population.
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 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
FGFR2 c.1223A>C
PM2 + BP4
→
VUS
Gene diagram
· NM_000141.4 · variants mapped to exon structure
FGFR2
NM_000141.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 20 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant not observed in the general population.
Absent from gnomAD v2.1 (exomes).Absent from gnomAD v4.1 (exomes/genomes).Absent from gnomAD-Canada v1.0 (genomes).
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.377 (below 0.5 threshold), BayesDel score is -0.0395 (in the benign range), and SpliceAI predicts no splicing impact (max delta score 0.00).
REVEL score 0.377 suggests no damaging effect.BayesDel score -0.0395 is in the benign prediction range.SpliceAI max delta 0.00 predicts no splice alteration.
Assessed · not applied
Pathogenic
PS1
No ClinVar entry exists for any variant causing the same amino acid change (p.Asp408Ala) at this position.
PS2
No de novo data available.
PS3
No functional studies identified for this variant or for a systematically characterized range that includes p.Asp408.
PS4
No case-control data available.
PM1
Residue 408 (Asp408) lies in the intracellular juxtamembrane region of FGFR2 between the transmembrane domain (~378-398) and the kinase domain (~481-754), which is not a recognized mutational hotspot for FGFR2-related disorders.
PM5
No same-residue comparator variants identified at position 408 in ClinVar.
PM6
No de novo reports (assumed de novo without confirmation of paternity/maternity) available for this variant in the evidence packet.
PP1
No cosegregation data available.
PP2
gnomAD missense constraint metrics (Z-score, o/e ratio) for FGFR2 are not available in the evidence packet.
PP3
Multiple in silico predictors do not support a deleterious effect.
PP4
No patient phenotype or family history data are available for disease specificity assessment.
PP5
No reputable source has recently reported this variant as pathogenic.
Benign
BA1
Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS2
No evidence of this variant observed in healthy adult individuals for FGFR2-related disorders with expected full penetrance at an early age.
BS3
No well-established in vitro or in vivo functional studies showing no damaging effect for this variant.
BS4
No segregation data available to demonstrate lack of segregation with disease in affected family members.
BP2
No data on observations of this variant in trans with a pathogenic variant for this dominantly inherited disorder, or in cis with a pathogenic variant in any inheritance pattern.
BP5
No case has been reported where this variant was found in an individual with an alternate molecular basis for disease.
BP6
No reputable source has recently reported this variant as benign.
N/A · 6
PVS1 · PM3 · PM4 · BP1 · BP3 · BP7
Research & evidence
Population frequency
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.377. BayesDel score = -0.0395299.
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. FGFR2, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancer types.
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.
Sources & reference links