Variant classification summary

NM_000141.4:c.819C>G

FGFR2 · NP_000132.3:p.(Asp273Glu) · NM_000141.4

GRCh37: chr10:123279613 G>C · GRCh38: chr10:121520099 G>C

Gene: FGFR2 Transcript: NM_000141.4

Final call

VUS

PM2 supporting BP4 supporting

Variant details

Gene

FGFR2

Transcript

NM_000141.4

Protein

NP_000132.3:p.(Asp273Glu)

gnomAD AF

1.239095955590801e-06 (v4.1)

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): extremely rare in gnomAD v4.1, with no observed homozygotes and absent from gnomAD-Canada v1.0.

2

BP4 (Supporting): REVEL 0.129 and SpliceAI max delta 0.007 concordantly predict no deleterious effect.

3

VUS: with only PM2 (supporting) and BP4 (supporting) met, the generic ACMG/AMP 2015 combination rules do not reach pathogenic or benign classification.

Final determination: 1 PM supporting + 1 BP supporting satisfies no P/LP/B/LB combining rule under generic ACMG/AMP 2015, so VUS.

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: this missense change does not produce a null allele, so the loss-of-function criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: no established pathogenic variant producing the same p.Asp273Glu change via a different nucleotide substitution is documented.	clinvar
PS2	Not assessed	Not assessed: no de novo occurrence of this variant in an affected proband with confirmed parentage is documented.
PS3	Not assessed	Not assessed: no functional assay data for this variant were available.
PS4	Not assessed	Not assessed: no case-control or cohort enrichment data for this variant were available.
PM1	Not assessed	Not assessed: no curated domain or hotspot annotation was available to evaluate residue 273 against a critical FGFR2 region.
PM2	Met	Met (supporting): extremely rare in gnomAD v4.1 with no observed homozygotes, and absent from gnomAD-Canada v1.0.	gnomad_v2 gnomad_v4 gnomad_canada
PM3	Not assessed	Not assessed: no evidence of this variant in trans with a second pathogenic FGFR2 variant was available.	PMID:25741868
PM4	N/A	Not applicable: this missense change does not alter protein length, so this criterion does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no other missense change at codon 273 with an established pathogenic classification is documented.	pm5_candidates
PM6	Not assessed	Not assessed: no presumed de novo occurrence of this variant in an affected proband is documented.
PP1	Not assessed	Not assessed: no family segregation or informative genotype data were available.
PP2	Not assessed	Not assessed: FGFR2 missense constraint and the proportion of benign missense variants could not be verified from available data.
PP3	Not met	Not met: REVEL score 0.129 and SpliceAI max delta 0.007 predict no damaging or splice-altering effect.	revel spliceai
PP4	Not assessed	Not assessed: no proband phenotype or clinical diagnosis was available to evaluate phenotypic specificity.
PP5	Not met	Not met: no ClinVar expert-panel Pathogenic/Likely pathogenic submission exists for this exact variant.	clinvar
BA1	Not met	Not met: the observed allele frequency is far below the stand-alone benign frequency threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Not met: the variant's population frequency is far too low to exceed the threshold expected for a benign FGFR2 allele.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no homozygotes and no phenotype-annotated healthy adult observations were available.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no functional assay data were available to confirm a wild-type-range effect.
BS4	Not assessed	Not assessed: no non-segregation evidence in affected or unaffected relatives was available.
BP1	Not assessed	Not assessed: whether truncating variants are the primary FGFR2 disease mechanism could not be determined from available data.	pvs1_gene_context
BP2	Not assessed	Not assessed: no second pathogenic FGFR2 variant or phase information was available.	PMID:25741868
BP3	N/A	Not applicable: this missense change is not an in-frame insertion or deletion in a repeat region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Met	Met (supporting): REVEL score 0.129 and SpliceAI max delta 0.007 concordantly predict no deleterious effect.	revel spliceai
BP5	Not assessed	Not assessed: no evidence of an alternate molecular diagnosis explaining the phenotype was available.
BP6	Not met	Not met: no ClinVar expert-panel Benign/Likely benign submission exists for this exact variant.	clinvar
BP7	N/A	Not applicable: this criterion applies to synonymous variants, and this is a missense change.	generic_acmg_combination_rules

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