10-121520163-G-C
Variant summary
The NM_000141.5(FGFR2):c.755C>G (p.Ser252Trp) variant causes a missense change involving the alteration of a conserved nucleotide. The gene FGFR2 is a tumor suppressor gene (CancerMine: 5 TSG, 46 oncogene, 36 driver citations). The gene FGFR2 is a known oncogene (CancerMine: 5 TSG, 46 oncogene, 36 driver citations). The gene FGFR2 is a cancer driver gene (CancerMine: 5 TSG, 46 oncogene, 36 driver citations). The variant is absent from the gnomAD population database at sites with sufficient sequencing coverage. In-silico predictor (REVEL) classifies this variant as likely damaging/oncogenic. Splicing prediction tools (SpliceAI) predict no significant impact on normal splicing. The affected nucleotide is highly conserved across species (PhyloP 100-way vertebrate score: 9.99). Variant has been reported in ClinVar as Pathogenic/Likely Pathogenic (★★). ClinVar reports functional evidence for this variant: "SCV000883242: PS3 upgraded in strength to Very Strong (https://www.ncbi.nlm.nih.gov/pubmed/14499350) (https://www.ncbi.nlm.nih.gov/pubmed/24489893) (https://www.ncbi.nlm.nih.gov/pubmed/15975938)." and additional evidence is available in ClinVar. A different missense at the same amino acid position has been reported as Pathogenic/Likely Pathogenic in ClinVar: p.S252F: Likely_pathogenic (ClinVar VariationId 13279, 1 star) Other variants at the same amino acid position have been reported in ClinVar (not pathogenic): p.S252L: Conflicting_classifications_of_pathogenicity (ClinVar VariationId 549484); p.S252= (synonymous): Likely_benign (ClinVar VariationId 1113095, 1 star); p.S252Y: Uncertain_significance (ClinVar VariationId 4724910, 1 star) This exact variant is established as oncogenic in: ClinVar, CGI (Cancer Genome Interpreter). The variant position is a cancer hotspot (cancerhotspots.org): 22 samples carry this exact amino acid change out of 66 samples with a variant at this residue. The variant has been observed in cBioPortal in 393 samples across 27 studies and 28 cancer types; somatic enrichment level: MODERATE (Observed in many cases across multiple studies/cancer contexts.). This exact variant is curated in the UniProt human variants database as Uncertain Significance; it is also listed as a COSMIC curated somatic variant.
Frequency
Consequence
NM_000141.5 missense
Scores
Clinical Significance
Conservation
Publications
- Apert syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
- Beare-Stevenson cutis gyrata syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
- bent bone dysplasia syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
- Crouzon syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, Genomics England PanelApp, G2P, Orphanet
- Jackson-Weiss syndromeInheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
- LADD syndrome 1Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
- Pfeiffer syndromeInheritance: AD Classification: DEFINITIVE, STRONG Submitted by: PanelApp Australia, Ambry Genetics, ClinGen, Genomics England PanelApp, G2P, Labcorp Genetics (formerly Invitae)
- Antley-Bixler syndrome without genital anomalies or disordered steroidogenesisInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
- familial scaphocephaly syndrome, McGillivray typeInheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
- Saethre-Chotzen syndromeInheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
- Antley-Bixler syndromeInheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- LADD syndromeInheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
- Pfeiffer syndrome type 1Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Pfeiffer syndrome type 2Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- Pfeiffer syndrome type 3Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
- acinar dysplasia caused by mutation in FGFR2Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia
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Classification according to ACGS-UK Somatic Oncogenicity v2025
Our verdict: Pathogenic. The variant received 19 points.
| Apply | Criterion Code & Title / Strength | Rationale / Clinical Context | |
|---|---|---|---|
| O1Established oncogenic variant | ClinVar oncogenic AND CGI oncogenic — two independent sources, Very Strong (O1); ClinVar oncogenic/SCI T1 (multiple submitters, ★★) — Strong (O1); ClinVar oncogenic/SCI T1 (single/no review, ★0–1) — Moderate (O1); TSG gene: ClinVar germline P/LP ★★+ — Moderate (O1); O1 contributing sources (8.0 pts): ClinVar (somatic oncogenic/LO (★★)), CGI (Cancer Genome Interpreter), ClinVar germline P/LP in TSG (★★) | ||
| O3Absent or very rare in population | Absent or extremely rare in gnomAD (AC ≤ 2) — O3 moderate; GnomAD: AF = absent, AC = 0 — absent/extremely rare (O3 moderate [+2]) | ||
| O4Enriched in somatic variant database | Enriched in cBioPortal (pre-computed score ≥ 2.0) — Moderate (O4); cBioPortal: samples=393 | studies=27 | cancer types=28 | level=MODERATE | points=2.0 | reason: Observed in many cases across multiple studies/cancer contexts. | ||
| O5Same location/impact as known oncogenic | Different AA at same residue with oncogenic evidence (or germline P/LP in TSG), or same AA change SCI Tier II Potential — Supporting (O5); ClinVar same-AA oncogenic/T1: false | ClinVar same-AA SCI tier: — | CGI same-AA oncogenic: false | TSG: true | ClinVar same-AA germline P/LP: false | CIViC LOF: false | ClinVar diff-AA oncogenic: false | ClinVar diff-AA germline P/LP: true | ||
| O6Computational evidence supports deleterious effect | Computational evidence supports a deleterious/oncogenic effect; Missense variant — primary computational scorer supports an oncogenic/deleterious effect | ||
| O7Mutational hotspot or critical domain | Strong hotspot (cancerhotspots.org): >50 total samples, ≥10 same AA change; Note: exclude MSK/TCGA-derived samples from cancerhotspots count to avoid double-counting with O4; cancerhotspots.org: total samples at AA position = 66, same AA change = 22; Exclude MSK/TCGA-derived samples from count to avoid double-counting with O4; UniProt domain: 0 pathogenic, 0 benign.; ±8 AA neighbourhood: 4 pathogenic, 0 benign (OR vs. background: 45.0); Variant does not impact splicing — splice-hotspot path not applicable | ||
| O8Missense constraint in gene or region | Missense in gene/domain constrained for missense variation where missense is common disease mechanism (O8 supporting); Gene/disease mechanism: missense is a common mechanism of oncogenesis; gnomAD missense Z-score: 4.45 (threshold ≥3.09 for constraint); Domain-level constraint: variant is in a critically constrained functional domain (IS_AT_CRITICAL_DOMAIN) |
Variant Effect in Transcripts
Automated classification analysis was done for transcript: NM_000141.5. You can select a different transcript below to see updated classification assignments.
RefSeq Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
FGFR2 | MANE Plus Clinical | c.755C>G p.Ser252Trp | missense | Exon 7 of 18 | Prot: NP_075259.4 UniProt: | |
FGFR2 | MANE Select | c.755C>G p.Ser252Trp | missense | Exon 7 of 18 | Prot: NP_000132.3 UniProt: | |
FGFR2 | c.755C>G p.Ser252Trp | missense | Exon 7 of 18 | Prot: NP_001428016.1 UniProt: |
Ensembl Transcripts
| Sel. | Gene / Transcript | Tags | HGVSc / HGVSp | Effect | Exon rank | Protein / UniProt |
|---|---|---|---|---|---|---|
FGFR2 | TSL:1MANE Plus Clinical | c.755C>G p.Ser252Trp | missense | Exon 7 of 18 | Prot: ENSP00000410294.2 UniProt: | |
FGFR2 | TSL:1MANE Select | c.755C>G p.Ser252Trp | missense | Exon 7 of 18 | Prot: ENSP00000351276.6 UniProt: | |
FGFR2 | TSL:1 | c.755C>G p.Ser252Trp | missense | Exon 6 of 17 | Prot: ENSP00000358052.1 UniProt: |
Frequencies
Allele frequencies (AF), counts (AC/AN), homozygotes and coverage
| Source / population | AF | AC | Hom | AN | Coverage |
|---|---|---|---|---|---|
Global population databases 4 sources | |||||
GnomAD3 genomes | Cov:33 | ||||
GnomAD2 exomes | AF: 0.00000400 | AC:1 | AN:249864 | ||
GnomAD4 exome | Cov:31 | ||||
GnomAD4 genome | Cov:33 | ||||
ClinVar
Computational Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
AlphaGenome AVI | Pathogenic | 31 | |
AlphaMissense | Pathogenic | 0.99 | |
BayesDel_addAF | Pathogenic | 0.32 | D |
BayesDel_noAF | Pathogenic | 0.41 | |
CADD | Pathogenic | 33 | |
DANN | Uncertain | 0.99 | |
DEOGEN2 | Pathogenic | 0.93 | D |
Eigen | Pathogenic | 0.88 | |
Eigen_PC | Pathogenic | 0.80 | |
FATHMM_MKL | Pathogenic | 0.98 | D |
GPN-Star LLR | N/A | -11 | |
GPN-Star score | N/A | 11 | |
LIST_S2 | Pathogenic | 0.99 | D |
M_CAP | Uncertain | 0.19 | D |
MetaRNN | Pathogenic | 0.96 | D |
MetaSVM | Uncertain | 0.63 | D |
Mutation Taster | N/A | 0/100 | disease causing (ClinVar) |
MutationAssessor | Pathogenic | 3.4 | M |
PhyloP100 | Pathogenic | 10 | |
popEVE | Uncertain | -4.7 | |
PrimateAI | Uncertain | 0.74 | T |
PROVEAN | Pathogenic | -6.0 | D |
RBP_binding_hub_radar | N/A | 0.0 | |
RBP_regulation_power_radar | N/A | 1.7 | |
REVEL | Pathogenic | 0.80 | |
Sift | Pathogenic | 0.0 | D |
Sift4G | Benign | 0.18 | T |
Varity_R | N/A | 0.83 | |
VESM-3B | Benign | -13 |
Splicing Scores
| Algorithm | Calibrated pred. | Score | Prediction |
|---|---|---|---|
Pangolin (max) | Benign | 0.010 | |
SpliceAI score (max) | Benign | 0.0 | Details are displayed if max score is > 0.2 |
Find out detailed SpliceAI scores and Pangolin per-transcript scores at
MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.