Classification rationale

PM2PP3 VUS

FGFR2 c.1516G>T

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.

PM2 + PP3 → VUS

Gene diagram · NM_000141.4 · variants mapped to exon structure

FGFR2 NM_000141.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate Pathogenic

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 v4.1: total AF 3.717e-06 (0.00037%), max subpopulation (East Asian) AF 6.682e-05 (0.00668%), grpmax FAF 1.772e-05, all below 0.1% PM2 thresholdgnomAD v2.1 (GRCh37 10-123260385-C-A): absentgnomAD-Canada v1.0: absent

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

PP3 supporting Pathogenic

Met (supporting): REVEL 0.667 and BayesDel noAF 0.100 both fall in the supporting-pathogenic tiers, two concordant computational lines.

REVEL score 0.667 (local lookup, revel-v1.3, chrom 10 pos 121500871 C>A) - ClinGen SVI-calibrated pathogenic supporting tier (>=0.644, verified against PMID 36413997); predicts deleterious missense effectBayesDel noAF score 0.100039 (local lookup, BayesDel_170824_noAF_chr10) - supporting-pathogenic tier (>=0.06) in the pipeline SVCv4 ladder (placeholder calibration); predicts deleterious missense effect, concordant with REVELSpliceAI max delta score 0.00 (DS_AG=DS_AL=DS_DG=DS_DL=0.0, variant_consequence=sequence_variant) - no predicted splice impact; neutral for PP3, does not contradict the missense deleterious predictions

spliceai ↗

Assessed · not applied

Pathogenic

PS1 Not met: no previously established pathogenic variant producing p.Asp506Tyr exists; the variant is absent from ClinVar.

PS2 Not assessed: no proband or parental-testing data were available to establish a de novo occurrence.

PS3 Not assessed: no functional assay evidence exists for this variant; in silico predictions do not qualify as functional studies.

PS4 Not assessed: no case-control or cohort data exist; the variant is absent from ClinVar.

PM1 Not met: residue 506 is not in a statistically significant Cancer Hotspots region, and no domain-boundary annotation was available.

PM5 Not assessed: no established pathogenic missense at residue 506 besides p.Asp506Tyr was available for comparison.

PM6 Not assessed: no proband or parental sequencing data exist to support an assumed de novo event.

PP1 Not assessed: no family or segregation data exist for this variant.

PP2 Not assessed: missense is a common FGFR2 disease mechanism, but no missense-constraint metric (e.g., gnomAD Z-score) was available.

PP4 Not assessed: no proband phenotype or family-history data were available.

PP5 Not met: no ClinVar expert-panel classification exists for this variant; it is absent from ClinVar.

Benign

BA1 Not met: highest population frequency 0.00668% (East Asian), far below the 1% BA1 threshold.

BS1 Not met: highest subpopulation frequency 0.00668%, more than 40-fold below the 0.3% BS1 threshold.

BS2 Not met: no homozygous carriers in gnomAD v4.1 (0 homozygotes across 1,614,106 alleles).

BS3 Not assessed: no functional studies demonstrating a lack of damaging effect were available.

BS4 Not assessed: no family testing data exist to evaluate non-segregation.

BP1 Not met: FGFR2 germline disease is caused by activating missense variants, so missense is a major disease mechanism.

BP2 Not met: no proband, phasing, or co-occurrence data exist; only population allele counts were observed.

BP4 Not met: REVEL 0.667 and BayesDel 0.100 both predict a deleterious effect, contradicting a no-impact call.

BP5 Not assessed: no proband data exist to determine whether an alternate molecular cause of disease is present.

BP6 Not met: no ClinVar expert-panel benign classification exists; the variant is absent from ClinVar.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 3.71723e-06; MAF= 0.00037%, 6/1614106 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 6.68151e-05; MAF= 0.00668%, 3/44900 alleles, homozygotes = 0); grpmax FAF= 1.772e-05.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

0.00037% · 6 / 1,614,106
0 hom · FAF 0.0018%

East Asian 3 / 44,900	0.0067%
Remaining individuals 3 / 62,490	0.0048%

+ 8 not observed (Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.667. BayesDel score = 0.100039.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FGFR2, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots