NM_000141.4:c.1516G>T

FGFR2 · NP_000132.3:p.(Asp506Tyr) · NM_000141.4

GRCh37: chr10:123260385 C>A · GRCh38: chr10:121500871 C>A

Gene: FGFR2 Transcript: NM_000141.4

Final call

VUS

PM2 moderate PP3 supporting

Variant details

Gene

FGFR2

Transcript

NM_000141.4

Protein

NP_000132.3:p.(Asp506Tyr)

gnomAD AF

3.7172279887442337e-06 (v4.1)

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

PM2 (Moderate): variant is absent from gnomAD v2.1 and gnomAD-Canada, with a gnomAD v4.1 total allele frequency of 0.00037%, far below the 0.1% PM2 threshold.

PP3 (Supporting): REVEL 0.667 and BayesDel noAF 0.100 both fall in the supporting-pathogenic tiers, providing two concordant computational lines for a deleterious effect.

Overall classification: VUS, because one moderate (PM2) plus one supporting (PP3) does not satisfy any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination in the generic ACMG/AMP 2015 rules.

Final determination: Under the generic ACMG/AMP 2015 fallback (no FGFR2 CSPEC/VCEP exists), the applied combination of 1 moderate (PM2) plus 1 supporting (PP3) pathogenic criterion does not meet any Pathogenic, Likely Pathogenic, Benign, or Likely Benign combination threshold, 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: c.1516G>T is a missense substitution (p.Asp506Tyr), not a null variant, so no loss-of-function mechanism applies.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not met	Not met: no previously established pathogenic variant producing p.Asp506Tyr exists; the variant is absent from ClinVar.	clinvar pm5_candidates
PS2	Not assessed	Not assessed: no proband or parental-testing data were available to establish a de novo occurrence.
PS3	Not assessed	Not assessed: no functional assay evidence exists for this variant; in silico predictions do not qualify as functional studies.	generic_acmg_combination_rules oncokb spliceai revel bayesdel
PS4	Not assessed	Not assessed: no case-control or cohort data exist; the variant is absent from ClinVar.
PM1	Not met	Not met: residue 506 is not in a statistically significant Cancer Hotspots region, and no domain-boundary annotation was available.
PM2	Met	Met (moderate): absent from gnomAD v2.1 and gnomAD-Canada; gnomAD v4.1 total allele frequency 0.00037%, far below the 0.1% threshold.	gnomad_v2 gnomad_v4 gnomad_canada generic_acmg_combination_rules
PM3	N/A	Not applicable: FGFR2 germline disease is autosomal dominant, so the recessive trans-phase requirement does not apply.	generic_acmg_combination_rules final_classification_framework pvs1_gene_context clinvar gnomad_v4
PM4	N/A	Not applicable: a missense substitution causes no change in protein length.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no established pathogenic missense at residue 506 besides p.Asp506Tyr was available for comparison.	clinvar pm5_candidates
PM6	Not assessed	Not assessed: no proband or parental sequencing data exist to support an assumed de novo event.
PP1	Not assessed	Not assessed: no family or segregation data exist for this variant.
PP2	Not assessed	Not assessed: missense is a common FGFR2 disease mechanism, but no missense-constraint metric (e.g., gnomAD Z-score) was available.	pvs1_gene_context
PP3	Met	Met (supporting): REVEL 0.667 and BayesDel noAF 0.100 both fall in the supporting-pathogenic tiers, two concordant computational lines.	revel bayesdel spliceai generic_acmg_combination_rules
PP4	Not assessed	Not assessed: no proband phenotype or family-history data were available.
PP5	Not met	Not met: no ClinVar expert-panel classification exists for this variant; it is absent from ClinVar.	clinvar
BA1	Not met	Not met: highest population frequency 0.00668% (East Asian), far below the 1% BA1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	Not met: highest subpopulation frequency 0.00668%, more than 40-fold below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	Not met: no homozygous carriers in gnomAD v4.1 (0 homozygotes across 1,614,106 alleles).	gnomad_v4 gnomad_v2 clinvar
BS3	Not assessed	Not assessed: no functional studies demonstrating a lack of damaging effect were available.	generic_acmg_combination_rules oncokb spliceai revel bayesdel
BS4	Not assessed	Not assessed: no family testing data exist to evaluate non-segregation.
BP1	Not met	Not met: FGFR2 germline disease is caused by activating missense variants, so missense is a major disease mechanism.	pvs1_gene_context
BP2	Not met	Not met: no proband, phasing, or co-occurrence data exist; only population allele counts were observed.	generic_acmg_combination_rules final_classification_framework clinvar gnomad_v4 gnomad_v2 gnomad_canada
BP3	N/A	Not applicable: a missense substitution does not alter protein length within a repetitive region.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.667 and BayesDel 0.100 both predict a deleterious effect, contradicting a no-impact call.	spliceai revel bayesdel generic_acmg_combination_rules
BP5	Not assessed	Not assessed: no proband data exist to determine whether an alternate molecular cause of disease is present.
BP6	Not met	Not met: no ClinVar expert-panel benign classification exists; the variant is absent from ClinVar.	clinvar
BP7	N/A	Not applicable: the variant is a missense change, not a synonymous variant.	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.