Classification rationale

PM2 BP4 VUS

FGFR2 c.346G>A

PM2 (Supporting): allele frequency 1.24e-06 (2/1,614,194 alleles) is far below the 0.1% threshold, and the variant is absent from gnomAD v2.1. BP4 (Supporting): REVEL 0.26, BayesDel -0.24425, and SpliceAI max delta 0.09 all predict no impact on the gene product. VUS: one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) conflict and satisfy no ACMG/AMP 2015 combination rule.

PM2 + BP4 → VUS

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

FGFR2 NM_000141.4

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 19 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

Met (supporting): allele frequency 1.24e-06 (2/1,614,194 alleles, 0.00012%) is far below the 0.1% threshold, and the variant is absent from gnomAD v2.1.

gnomad_v4gnomad_v2gnomad_canada

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Met (supporting): REVEL 0.26 (benign-supporting band 0.183-0.290), BayesDel -0.24425, and SpliceAI max delta 0.09 (below 0.2) all predict no impact.

REVEL score 0.26 (local lookup, revel-v1.3) - benign-supporting band (0.183-0.290) per ClinGen SVI calibration verified against PMID 36413997; supports no impact on FGFR2BayesDel noAF score -0.24425 (local lookup, BayesDel_170824_noAF_chr10) - benign-supporting tier (-0.36 to -0.18) per pipeline SVCv4 ladder (placeholder calibration); supports no impact, concordant with REVELSpliceAI max delta score 0.09 (DS_AG 0.0, DS_AL 0.09, DS_DG 0.09, DS_DL 0.07; variant_consequence=sequence_variant) - below the 0.2 splice-impact threshold; no predicted splice impact for this exonic missense

spliceai ↗

Assessed · not applied

Pathogenic

PS1 Not assessed: no established pathogenic variant producing p.Glu116Lys is documented in ClinVar or the literature.

PS2 Not assessed: no proband genotype, parental testing, or de novo evidence is available for this variant.

PS3 Not assessed: no well-established functional study of p.Glu116Lys was available.

PS4 Not assessed: no case-control or affected-cohort data exist; the only occurrence is 3 somatic cancer entries in COSMIC.

PM1 Not met: p.Glu116 is not a statistically significant mutation hotspot, and no source places it in a critical functional domain.

PM5 Not assessed: no different pathogenic missense at p.Glu116 (e.g., p.Glu116Val) is documented in ClinVar or the literature.

PM6 Not assessed: no de novo occurrence of c.346G>A is documented in any proband.

PP1 Not assessed: no family or pedigree data exist to evaluate co-segregation of c.346G>A with disease.

PP2 Not assessed: FGFR2 missense variants are a known disease mechanism, but missense constraint metrics needed for the second prong are unavailable.

PP3 Not met: all computational lines are neutral - SpliceAI max delta 0.09 vs 0.2, REVEL 0.26 vs 0.644, BayesDel -0.24425 - so no deleterious effect is predicted.

PP4 Not assessed: no proband phenotype or family history is available to evaluate phenotype specificity.

Benign

BA1 Not met: highest observed allele frequency is 1.69e-06 (0.00017%), roughly 4 orders of magnitude below the 1% BA1 threshold.

BS1 Not met: observed allele frequency 1.24e-06 (0.00012%) is over 3 orders of magnitude below the 0.3% BS1 threshold.

BS2 Not met: only 2 heterozygous carriers (0 homozygotes) among 1,614,194 alleles, far short of the multiple healthy-adult observations BS2 requires.

BS3 Not assessed: no functional study showing absence of a damaging effect is available; in silico predictions do not qualify.

BS4 Not assessed: no family data exist to evaluate non-segregation of the variant.

BP1 Not met: FGFR2 disease is caused by activating missense variants, not truncating variants, so BP1's premise does not apply.

BP2 Not assessed: no proband observation with phase information relative to a pathogenic FGFR2 variant is available.

BP5 Not assessed: no proband molecular workup exists to establish an alternate molecular basis for disease.

N/A · 7 PVS1 · PM3 · PM4 · PP5 · BP3 · BP6 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 1.23901e-06; MAF= 0.00012%, 2/1614194 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 1.69485e-06; MAF= 0.00017%, 2/1180042 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.

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

0.00012% · 2 / 1,614,194
0 hom · FAF 2.8e-05%

European (non-Finnish)

2 / 1,180,042

0.00017%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)

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 = 0.09). REVEL score = 0.26. BayesDel score = -0.24425.

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 previously been reported in somatic cancers (COSMIC; COSV60640640, n = 3 times).

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