Variant classification summary

NM_000141.4:c.2383G>A

FGFR2 · NP_000132.3:p.(Asp795Asn) · NM_000141.4

GRCh37: chr10:123239454 C>T · GRCh38: chr10:121479940 C>T

Gene: FGFR2 Transcript: NM_000141.4

Final call

VUS

PM2 supporting

Variant details

Gene

FGFR2

Transcript

NM_000141.4

Protein

NP_000132.3:p.(Asp795Asn)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 (Supporting): variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with no reported allele frequency or homozygotes.

2

Overall: VUS — the single supporting-strength criterion (PM2) does not satisfy any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination rule under generic ACMG/AMP 2015.

Final determination: Generic ACMG/AMP 2015 fallback: with only PM2 (supporting) met and no other criteria met, none of the Pathogenic/Likely Pathogenic/Benign/Likely Benign combination thresholds are reached, 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	Not applicable: this missense change triggers no null-variant mechanism such as nonsense-mediated decay or truncation.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: the variant is absent from ClinVar, and no established pathogenic change producing the same amino acid substitution was available.	clinvar
PS2	Not assessed	Not assessed: no parental testing or trio data were provided to evaluate a de novo occurrence.
PS3	Not assessed	Not assessed: no functional assay results (e.g., kinase activity or signaling) for this variant were available.
PS4	Not assessed	Not assessed: no case-control cohort or affected-case enrichment data for this variant were available.
PM1	Not assessed	Not assessed: the variant is not in a statistically significant cancer hotspot, and no domain or benign-variation-density data were available.
PM2	Met	Met (supporting): absent from gnomAD v2.1, v4.1, and gnomAD-Canada, with no reported allele frequency or homozygotes.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	Not assessed	Not assessed: no affected-proband or phase data were available to evaluate a pathogenic variant in trans.
PM4	N/A	Not applicable: missense change does not alter protein length, so the in-frame indel/stop-loss premise does not apply.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no pathogenic missense at residue Asp795 was available as a comparator.	pm5_candidates
PM6	Not assessed	Not assessed: no family or case-report data suggest an unconfirmed de novo occurrence.
PP1	Not assessed	Not assessed: no pedigree or segregation data were available.
PP2	Not assessed	Not assessed: activating missense is a known FGFR2 disease mechanism, but no missense-constraint or benign-variation-rate data were available.	pvs1_gene_context
PP3	Not met	Not met: REVEL 0.522 is below the >=0.644 supporting threshold, and SpliceAI max delta 0.103 is below 0.2.	revel spliceai bayesdel
PP4	Not assessed	Not assessed: no patient phenotype or clinical diagnosis was provided.
PP5	Not met	Not met: the variant is absent from ClinVar, so no expert-panel pathogenic assertion exists.	clinvar
BA1	Not met	Not met: the variant is absent from population databases, with no allele frequency approaching the >5% benign threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS1	Not assessed	Not assessed: no disease-specific allele-frequency threshold model was available.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS2	Not assessed	Not assessed: no healthy-adult cohort or documented homozygous individuals were available.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
BS3	Not assessed	Not assessed: no functional assay results were available to evaluate normal protein activity.
BS4	Not assessed	Not assessed: no data from unaffected relatives were available to establish non-segregation.
BP1	N/A	Not applicable: FGFR2 germline disease is driven by activating missense variants, not truncation, so this criterion does not apply.	pvs1_gene_context
BP2	Not assessed	Not assessed: no phase-resolved observation with a pathogenic variant was available.
BP3	N/A	Not applicable: this missense change is not an in-frame indel in a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.522 exceeds the <=0.290 BP4 threshold, and SpliceAI 0.103 sits in the indeterminate 0.1-0.2 zone.	revel spliceai bayesdel
BP5	Not assessed	Not assessed: no independent molecular diagnosis was available to evaluate an alternate cause of the phenotype.
BP6	Not met	Not met: the variant is absent from ClinVar, so no expert-panel benign assertion exists.	clinvar
BP7	N/A	Not applicable: this is a missense change, so the synonymous-variant premise does not apply.	generic_acmg_combination_rules

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.