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NM_000141.4:c.1516G>T
p.Asp506Tyr · FGFR2
ACMG/AMP
0%
complete
Final classification
VUS
PM2PP3
FGFR2
c.1516G>T
p.Asp506Tyr
missense
Gene context NCBI Gene ↗ OncoKB ↗

FGFR2 encodes a receptor tyrosine kinase in the fibroblast growth factor receptor family that binds fibroblast growth factors and activates signaling pathways (including PI3K/AKT and MAPK) that promote cell growth, division, and differentiation. Germline mutations in FGFR2 cause several inherited craniosynostosis syndromes — including Apert, Crouzon, Pfeiffer, Jackson-Weiss, Beare-Stevenson, and Saethre-Chotzen syndromes — in which the bones of the skull fuse prematurely. FGFR2 also plays an oncogenic role in cancer: somatic mutations, fusions, and amplifications of the gene have been found in endometrial, gastric, and breast cancers and ameloblastomas, and FGFR inhibitors are used as cancer therapies.

This variant

Germline FGFR2 mutations cause autosomal dominant craniosynostosis syndromes, usually through activating missense changes, and this variant is a missense substitution (p.Asp506Tyr) in the kinase-encoding region. Yet it is absent from ClinVar, has no functional or clinical evidence, and is not in a significant hotspot, so the two supporting computational signals are insufficient and it remains a variant of uncertain significance.

Transcript
NM_000141.4
HGVS · transcript:coding
NM_000141.4:c.1516G>T
GRCh38
chr10:121500871 C>A
GRCh37
chr10:123260385 C>A
VUS under generic ACMG/AMP 2015: only PM2 (moderate) and PP3 (supporting) are met, which does not reach any Pathogenic, Likely Pathogenic, or Benign combination threshold.
Classification rationale
PM2PP3 VUS
FGFR2 c.1516G>T missense

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
LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
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
MetEvidence satisfies this criterion.
Not metEvaluated against available evidence; threshold not reached.
Not assessedApplies in principle, but no evidence was found to evaluate it.
N/ADoesn't apply to this variant type.
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 · 10 not met · 11 not assessed
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 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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 screenshot
ClinVar
This variant is absent from ClinVar.
ClinVar ↗
SpliceAI screenshot
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 / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
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