NM_000141.4:c.1223A>C

FGFR2 · NP_000132.3:p.(Asp408Ala) · NM_000141.4

GRCh37: chr10:123274695 T>G · GRCh38: chr10:121515181 T>G

Gene: FGFR2 Transcript: NM_000141.4

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

FGFR2

Transcript

NM_000141.4

Protein

NP_000132.3:p.(Asp408Ala)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

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.

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).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, 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	Missense substitution (c.1223A>C, p.Asp408Ala); does not fall into PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. pvs1_variant_assessment confirms apply_generic_pvs1_framework=false.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No ClinVar entry exists for any variant causing the same amino acid change (p.Asp408Ala) at this position. There is no evidence that this amino acid change has been previously established as pathogenic regardless of the underlying nucleotide change.	clinvar
PS2	Not met	No de novo data available. No family trios or confirmed paternity/maternity de novo reports exist for this variant in the evidence packet.
PS3	Not met	No functional studies identified for this variant or for a systematically characterized range that includes p.Asp408. Literature search returned 0 PMIDs; OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence.	oncokb
PS4	Not met	No case-control data available. Variant is absent from ClinVar and no prevalence comparison between affected individuals and controls can be performed.	clinvar
PS5	N/A	PS5 is not a criterion in the ACMG/AMP 2015 classification framework used for this adjudication.
PM1	Not met	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. Cancerhotspots.org reports no statistical significance at this residue, and no ClinVar entries exist for position 408.	clinvar
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	Not met	No same-residue comparator variants identified at position 408 in ClinVar. PM5 candidate search returned 0 candidates; no pathogenic missense variant at Asp408 has been reported against which to apply PM5.	pm5_candidates clinvar
PM6	Not met	No de novo reports (assumed de novo without confirmation of paternity/maternity) available for this variant in the evidence packet.
PP1	Not met	No cosegregation data available. No family studies have been performed or reported for this variant.
PP2	Not assessed	gnomAD missense constraint metrics (Z-score, o/e ratio) for FGFR2 are not available in the evidence packet. While FGFR2-associated disorders are primarily caused by gain-of-function missense variants, PP2 requires quantitative evidence of low benign missense variation in the gene, which was not provided.
PP3	Not met	Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.377 (below the 0.5 threshold for damaging prediction), BayesDel score is -0.0395 (in the benign range), and SpliceAI predicts no splicing impact (max delta score 0.00).	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data are available for disease specificity assessment. The variant was submitted without clinical context.
PP5	Not met	No reputable source has recently reported this variant as pathogenic. The variant is absent from ClinVar and no publications mention it.	clinvar
BA1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No evidence of this variant observed in healthy adult individuals for FGFR2-related disorders with expected full penetrance at an early age.
BS3	Not met	No well-established in vitro or in vivo functional studies showing no damaging effect for this variant. No functional data of any kind were identified.	oncokb
BS4	Not met	No segregation data available to demonstrate lack of segregation with disease in affected family members.
BP1	N/A	FGFR2-associated disorders (craniosynostosis syndromes, skeletal dysplasias) are primarily caused by gain-of-function missense variants, not truncating variants. BP1 applies only to genes where truncating variants are the primary disease mechanism.	pvs1_gene_context
BP2	Not met	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.
BP4	Met	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 bayesdel spliceai
BP5	Not met	No case has been reported where this variant was found in an individual with an alternate molecular basis for disease.
BP6	Not met	No reputable source has recently reported this variant as benign. The variant is absent from ClinVar and no publications mention it.	clinvar
BP7	N/A	This is a missense variant (c.1223A>C, p.Asp408Ala), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	In-frame indels in repeat regions without known function — not applicable to this missense substitution.
PM3	N/A	FGFR2-related disorders follow autosomal dominant inheritance. PM3 (detected in trans for recessive disorders) is not applicable.
PM4	N/A	Protein length changes due to in-frame indels or stop-loss — not applicable to this missense substitution.

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