Variant classification summary

NM_000141.5:c.755C>G

FGFR2 · NP_000132.3:p.(Ser252Trp) · NM_000141.5

GRCh37: chr10:123279677 G>C · GRCh38: chr10:121520163 G>C

Gene: FGFR2 Transcript: NM_000141.5

Final call

Pathogenic

PS3 strong PS4 strong PM1 moderate PM2 supporting PM6 moderate PP1 supporting PP3 moderate

Variant details

Gene

FGFR2

Transcript

NM_000141.5

Protein

NP_000132.3:p.(Ser252Trp)

gnomAD AF

4.002177184388308e-06 (v2.1)

ClinVar

Pathogenic

OncoKB

Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

Pathogenic: PS3 strong shows an 8.6- to 36-fold increase in FGFR2 ligand affinity and altered receptor specificity.

2

Pathogenic: PS4 strong shows S252W in 45 of 70 Apert syndrome patients with an odds ratio of 224,875.8.

3

Pathogenic: PM1 moderate places residue 252 in a recurrent FGFR2 IgII-III linker hotspot.

4

Pathogenic: PM2 supporting shows an allele frequency of 1/249,864 in gnomAD v2.1 and absence in gnomAD v4.1.

5

Pathogenic: PM6 moderate is supported by reported negative parental samples and de novo occurrence.

6

Pathogenic: PP1 supporting is supported by reported disease segregation in several families.

7

Pathogenic: PP3 moderate is supported by a REVEL score of 0.796.

Final determination: Under the generic ACMG/AMP 2015 fallback, two strong pathogenic criteria (PS3 and PS4) satisfy the Pathogenic combination rule, and no benign rule is satisfied.

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	Not assessed	Not assessed: p.Ser252Trp is established, but no pathogenic alternate nucleotide change producing the same amino-acid substitution is documented.	PMID:11121055 PMID:11390973 PMID:15282208
PS2	Not met	Not met: de novo occurrence is reported, but confirmation of both maternity and paternity is not documented.	clinvar
PS3	Met	Met, strong: exact S252W increased FGFR2 ligand affinity 8.6- to 36-fold versus wild type in biochemical assays and altered receptor-ligand specificity.	PMID:15282208
PS4	Met	Met: 45/70 affected patients carried S252W versus approximately 1/124,932 gnomAD controls, yielding OR 224,875.8 (95% CI 29,829.1-1,695,297.5), above >5 with CI excluding 1.	gnomad_v2
PM1	Met	Met at moderate strength: residue 252 lies in the recurrent FGFR2 IgII–IgIII linker hotspot containing pathogenic Apert syndrome substitutions.	PMID:11121055 PMID:15282208
PM2	Met	Met at supporting: gnomAD v2.1 AF is 4.00218e-06 (1/249864), below the <=0.0001 PM2 threshold, and gnomAD v4.1 is absent.	gnomad_v2 gnomad_v4
PM3	N/A	Not applicable: FGFR2-related Apert syndrome is autosomal dominant, whereas PM3 requires a recessive disorder and a pathogenic variant confirmed in trans.	PMID:11121055
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: pathogenic p.Pro253Arg is adjacent, not same-residue, and no different pathogenic missense at Ser252 is documented.	PMID:11121055 PMID:11390973 PMID:15282208
PM6	Met	Met: parental samples were negative and the variant was reported de novo, without documented confirmation of maternity and paternity.	clinvar
PP1	Met	Met at supporting strength: segregation is reported in several families with multiple affected individuals, but family-level meiosis data are not provided.	clinvar
PP2	Not assessed	Not assessed: FGFR2 missense disease mechanism is documented, but gene-level low benign-missense variation is not established by the available population data.	PMID:15282208 gnomad_v2 gnomad_v4
PP3	Met	Met at moderate strength: missense REVEL score 0.796 meets the generic PP3 moderate threshold of >=0.773.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are unavailable, so specificity for a single genetic etiology cannot be judged.
PP5	Not met	Not met: exact-variant ClinVar is Pathogenic, but expert-panel submissions are 0, so non-expert assertions cannot trigger PP5.	clinvar
BA1	Not met	Not met: gnomAD v2.1 AF is 4.00218e-06 (0.000400%), far below the 0.05 BA1 threshold, and gnomAD v4.1 is absent.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: available AF is 4.00218e-06 (1/249864), far below the 0.01 default, with no grpmax FAF or credible-frequency calculation supporting excess frequency.	gnomad_v2 gnomad_v4 clinvar
BS2	Not assessed	Not assessed: gnomAD shows one allele but does not establish that the carrier was a phenotypically healthy adult, despite 0 homozygotes.	gnomad_v2 gnomad_v4 clinvar
BS3	Not assessed	Not assessed: available exact-variant assays show increased ligand binding, not a well-established normal protein-function or splicing result.	PMID:15282208
BS4	Not assessed	Not assessed: no affected family member lacking the variant is documented for evaluating lack of segregation.
BP1	Not met	Not met: FGFR2 craniosynostosis is driven by activating missense variants, including S252W, rather than primarily truncating variants.	PMID:15282208 PMID:11390973
BP2	Not assessed	Not assessed: no second pathogenic variant with documented cis/trans phase is provided for NM_000141.5:c.755C>G (p.Ser252Trp).
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 0.796 exceeds the generic BP4 supporting cutoff of <=0.29.	revel
BP5	Not assessed	Not assessed: no case report documents this variant alongside an alternate molecular basis for the patient's disease.
BP6	Not met	Not met: exact-variant ClinVar has no benign expert-panel classification and reports 0 expert-panel submissions.	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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