Variant classification summary

NM_000141.5:c.758C>G

FGFR2 · NP_000132.3:p.(Pro253Arg) · NM_000141.5

GRCh37: chr10:123279674 G>C · GRCh38: chr10:121520160 G>C

Gene: FGFR2 Transcript: NM_000141.5

Final call

Pathogenic

PS1 strong PS3 moderate PM6 moderate PM2 supporting PP3 supporting PP4 supporting

Variant details

Gene

FGFR2

Transcript

NM_000141.5

Protein

NP_000132.3:p.(Pro253Arg)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS1 strong is met for the previously established pathogenic p.Pro253Arg amino-acid change.

2

Pathogenic: PS3 moderate is met because exact-variant studies show increased FGF2 binding and an activating effect.

3

Pathogenic: PM6 moderate is met because the exact variant was absent from both tested parents.

4

Pathogenic: PM2 supporting is met because the variant is absent from gnomAD v2.1 and v4.1.

5

Pathogenic: PP3 supporting is met because REVEL is 0.724 under the adjudicated threshold.

6

Pathogenic: PP4 supporting is met from the exact-variant Apert syndrome phenotype with craniosynostosis and severe syndactyly.

Final determination: Under the generic ACMG/AMP 2015 fallback, 1 Strong plus 2 Moderate plus at least 2 Supporting pathogenic criteria supports a Pathogenic classification.

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: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Met	Met, strong: the exact p.Pro253Arg amino-acid change is previously established as pathogenic, and SpliceAI predicts minimal splice impact with a 0.001 maximum delta score.	clinvar PMID:11390973 PMID:23915865 spliceai
PS2	Not assessed	Not assessed: both parents lacked the variant, but confirmed maternity, paternity, and absence of family history are not documented for PS2.	PMID:23915865
PS3	Met	Met at moderate strength: exact p.Pro253Arg formed three additional FGF2 hydrogen bonds and showed an approximately 1.5-fold lower dissociation rate than wild-type FGFR2.	PMID:11390973 PMID:25741868
PS4	Not assessed	Not assessed: the affected series reports 25 Pro253Arg cases among 70 patients but lacks a matched control frequency, so OR/RR > 5.0 and its confidence interval cannot be calculated.
PM1	Not assessed	Not assessed: p.Pro253Arg is in a functionally important IgII–IgIII linker, but absence of benign variation across the qualifying region is not established.	PMID:11390973 clinvar hotspots
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, satisfying the generic PM2 threshold of 0.01% or lower.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	N/A	Not applicable: the reported FGFR2 p.Pro253Arg case is heterozygous and de novo, whereas PM3 is restricted to recessive disorders with a pathogenic variant in trans.	PMID:23915865
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no confirmed pathogenic different missense substitution at Pro253 was available in the collected evidence for comparison with p.Pro253Arg.	pm5_candidates clinvar
PM6	Met	Met: the exact variant was absent from both tested parents in a fetus with Apert syndrome, without documented maternity or paternity confirmation.	PMID:23915865
PP1	Not assessed	Not assessed: no multiple affected family members or informative co-segregating meioses are documented for this variant.
PP2	Not assessed	Not assessed: recurrent activating FGFR2 missense variants are documented, but a gene-level low benign-missense rate is not established by the available evidence.	PMID:11390973 gnomad_v2 gnomad_v4
PP3	Met	Met at supporting strength: missense REVEL score 0.724 exceeds the generic PP3 supporting threshold of 0.644.	revel
PP4	Met	Met: the exact variant is reported with Apert syndrome's characteristic craniosynostosis and severe syndactyly, a highly specific phenotype for this FGFR2-associated disorder.	PMID:23915865 PMID:11390973
PP5	Not met	Not met: the exact-variant ClinVar record has zero expert-panel submissions, so non-expert pathogenic assertions cannot trigger PP5.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than reaching the generic BA1 threshold of 5%.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: gnomAD v2.1 and v4.1 report no filtering allele frequency or grpmax FAF, so none exceeds the generic BS1 threshold of 1%.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no documented healthy adult carrier of the exact variant is available, despite its absence from population databases.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no exact-variant assay showed no damaging effect on FGFR2 protein function or splicing.
BS4	Not assessed	Not assessed: no affected relatives with genotype results are documented to demonstrate lack of segregation.
BP1	Not met	Not met: FGFR2 disease literature identifies recurrent activating missense substitutions, including Pro253Arg and Ser252Trp, rather than primarily truncating variants.	PMID:11390973 clinvar
BP2	Not assessed	Not assessed: the report documents a heterozygous de novo variant with parents negative, but provides no pathogenic second allele or cis/trans phase observation.	PMID:23915865
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: missense REVEL score 0.724 is above the generic BP4 supporting cutoff of 0.29.	revel
BP5	Not assessed	Not assessed: no sufficiently detailed exact-variant case documents an independent molecular cause explaining the patient's disease.
BP6	Not met	Not met: the exact-variant ClinVar record has zero expert-panel submissions and no Benign or Likely benign expert-panel classification.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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