chr10-121520163-G-A

Variant names:

• chr10-121520163-G-A
• rs79184941
• NM_022970.4:c.755C>T
• FGFR2 p.Ser252Leu

GermlineCancer (beta)

Variant summary

Our verdict is Likely pathogenic.

+9 Likely Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 9 classification points (ACGS-UK Somatic Oncogenicity v2025). O3_SupportingO4_ModerateO5_SupportingO7_StrongO8_Supporting

The NM_000141.5(FGFR2):c.755C>T (p.Ser252Leu) 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 allele was found at a cumulative frequency of 0.0000403 (AC=65) in the gnomAD database across 1,612,936 control chromosomes (no homozygotes observed). The grpmax filtering allele frequency (95% CI) is 0.0000377. 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 Benign/Likely Benign (no review stars). 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.S252= (synonymous): Likely_benign (ClinVar VariationId 1113095, 1 star); p.S252Y: Uncertain_significance (ClinVar VariationId 4724910, 1 star) A different missense variant at the same amino acid position has been reported as oncogenic in ClinVar. 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 26 samples across 13 studies and 11 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:
  • Genomes: 𝑓 0.000013 (0 hom., cov: 33)
  • Exomes 𝑓: 0.000043 (0 hom.)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Conflicting classifications of pathogenicity criteria provided, conflicting classifications U:5 B:4
• Conservation: PhyloP100: 9.99
• Publications: 20 publications found

Genes affected

FGFR2 (HGNC:3689): (fibroblast growth factor receptor 2) The protein encoded by this gene is a member of the fibroblast growth factor receptor family, where amino acid sequence is highly conserved between members and throughout evolution. FGFR family members differ from one another in their ligand affinities and tissue distribution. A full-length representative protein consists of an extracellular region, composed of three immunoglobulin-like domains, a single hydrophobic membrane-spanning segment and a cytoplasmic tyrosine kinase domain. The extracellular portion of the protein interacts with fibroblast growth factors, setting in motion a cascade of downstream signals, ultimately influencing mitogenesis and differentiation. This particular family member is a high-affinity receptor for acidic, basic and/or keratinocyte growth factor, depending on the isoform. Mutations in this gene are associated with Crouzon syndrome, Pfeiffer syndrome, Craniosynostosis, Apert syndrome, Jackson-Weiss syndrome, Beare-Stevenson cutis gyrata syndrome, Saethre-Chotzen syndrome, and syndromic craniosynostosis. Multiple alternatively spliced transcript variants encoding different isoforms have been noted for this gene. [provided by RefSeq, Jan 2009]

FGFR2 Gene-Disease associations (from GenCC):

• Apert syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
• Beare-Stevenson cutis gyrata syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, ClinGen, Genomics England PanelApp, G2P, PanelApp Australia
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, ClinGen, Labcorp Genetics (formerly Invitae), Orphanet
• Crouzon syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: PanelApp Australia, ClinGen, Ambry Genetics, Genomics England PanelApp, G2P, Orphanet
• Jackson-Weiss syndrome

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Genomics England PanelApp, G2P
• LADD syndrome 1

  Inheritance: AD Classification: DEFINITIVE, STRONG, MODERATE Submitted by: Labcorp Genetics (formerly Invitae), G2P, Ambry Genetics
• Pfeiffer syndrome

  Inheritance: 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 steroidogenesis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• familial scaphocephaly syndrome, McGillivray type

  Inheritance: AD Classification: STRONG, SUPPORTIVE Submitted by: Genomics England PanelApp, Orphanet
• Saethre-Chotzen syndrome

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp
• Antley-Bixler syndrome

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• LADD syndrome

  Inheritance: AD Classification: SUPPORTIVE, LIMITED Submitted by: Orphanet, ClinGen
• Pfeiffer syndrome type 1

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 2

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• Pfeiffer syndrome type 3

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• acinar dysplasia caused by mutation in FGFR2

  Inheritance: AR Classification: LIMITED Submitted by: PanelApp Australia

Classification according to ACGS-UK Somatic Oncogenicity v2025

Classification was made for transcript:

Our verdict: Likely_pathogenic. The variant received 9 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	O3Absent or very rare in population		Very rare in gnomAD (popmax AF <0.01%) — O3 supporting; GnomAD effective popmax AF = 0.000038 — very rare (O3 supporting [+1])
	O4Enriched in somatic variant database		Enriched in cBioPortal (pre-computed score ≥ 2.0) — Moderate (O4); cBioPortal: samples=26 | studies=13 | cancer types=11 | 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: true | ClinVar diff-AA germline P/LP: true
	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 NM_022970.4	MANE Plus Clinical	c.755C>T p.Ser252Leu	missense	Exon 7 of 18	Prot: NP_075259.4 UniProt:
	FGFR2 NM_000141.5	MANE Select	c.755C>T p.Ser252Leu	missense	Exon 7 of 18	Prot: NP_000132.3 UniProt:
	FGFR2 NM_001441087.1		c.755C>T p.Ser252Leu	missense	Exon 7 of 18	Prot: NP_001428016.1 UniProt:

FGFR2 NM_022970.4

MANE Plus Clinical

HGVSc / HGVSpc.755C>Tp.Ser252Leu

Exon rankExon 7 of 18

missense

Prot: NP_075259.4UniProt: P21802-3

FGFR2 NM_000141.5

MANE Select

HGVSc / HGVSpc.755C>Tp.Ser252Leu

Exon rankExon 7 of 18

missense

Prot: NP_000132.3UniProt: P21802-1

FGFR2 NM_001441087.1

HGVSc / HGVSpc.755C>Tp.Ser252Leu

Exon rankExon 7 of 18

missense

Prot: NP_001428016.1UniProt: P21802-18

Ensembl Transcripts

Sel.	Gene / Transcript	Tags	HGVSc / HGVSp	Effect	Exon rank	Protein / UniProt
	FGFR2 ENST00000457416.7	TSL:1MANE Plus Clinical	c.755C>T p.Ser252Leu	missense	Exon 7 of 18	Prot: ENSP00000410294.2 UniProt:
	FGFR2 ENST00000358487.10	TSL:1MANE Select	c.755C>T p.Ser252Leu	missense	Exon 7 of 18	Prot: ENSP00000351276.6 UniProt:
	FGFR2 ENST00000369056.5	TSL:1	c.755C>T p.Ser252Leu	missense	Exon 6 of 17	Prot: ENSP00000358052.1 UniProt:

FGFR2 ENST00000457416.7

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.755C>Tp.Ser252Leu

Exon rankExon 7 of 18

missense

Prot: ENSP00000410294.2UniProt: P21802-3

FGFR2 ENST00000358487.10

TSL:1MANE Select

HGVSc / HGVSpc.755C>Tp.Ser252Leu

Exon rankExon 7 of 18

missense

Prot: ENSP00000351276.6UniProt: P21802-1

FGFR2 ENST00000369056.5

TSL:1

HGVSc / HGVSpc.755C>Tp.Ser252Leu

Exon rankExon 6 of 17

missense

Prot: ENSP00000358052.1UniProt: P21802-17

Frequencies

Allele frequencies (AF), counts (AC/AN), homozygotes and coverage

Common (AF > 0.05 / Hom > 5)

Rare (AF ≤ 0.0001 / Hom ≤ 1)

Source / population	AF	AC	Hom	AN	Coverage
Global population databases 6 sources Large-scale international reference populations
GnomAD3 genomes	AF: 0.0000131	AC:2	Hom:0	AN:152202	Cov:33
GnomAD2 exomes	AF: 0.0000560	AC:14	Hom:	AN:249864	Cov:
GnomAD4 exome	AF: 0.0000431	AC:63	Hom:0	AN:1460734	Cov:31
GnomAD4 genome	AF: 0.0000131	AC:2	Hom:0	AN:152202	Cov:33
TOPMed (Bravo)	AF: 0.0000416	AC:	Hom:	AN:	Cov:
ALFA (dbGaP/dbSNP Allele Frequency Aggregator)	AF: 0.00	AC:0	Hom:0	AN:23232	Cov:
Local & regional cohorts 4 sources Population-specific and national genomic databases
ESP6500 (Exome Variant Server)	AF: 0.0000769	AC:1	Hom:	AN:13006	Cov:
Korea4K (4,157 Koreans)	AF: 0.000276	AC:2	Hom:	AN:7234	Cov:
ToMMo 61KJPN (+60KJPN MNV)	AF: 0.0000810	AC:10	Hom:0	AN:122782	Cov:
WBBC (Westlake BioBank for Chinese) pilot	AF: 0.000223	AC:2	Hom:0	AN:8960	Cov:

Showing 10 sources

Case/control cohorts

Cohort	Cases			Controls
	AF	AC	AN	AF	AC	AN
ASC(Autism)	0.00 *	0	11090	0.000114 *	2	17602
BipEx(Bipolar disorder (including schizoaffective))	0.00	0	28420	0.0000347	1	28844
Epi25(Epilepsy)	0.0000715	3	41958	0.0000299	2	66888
SCHEMA(Schizophrenia)	0.0000798	9	112852	0.0000631	12	190186

Showing 4 cohortsAllele count / allele number. AF is computed from the counts for ASC (not provided by the source).

ClinVar

ClinVar submissions

Significance: Conflicting classifications of pathogenicity

Revision: criteria provided, conflicting classifications

Pathogenic	VUS	Benign	Condition
-	-	3	Crouzon syndrome (3)
-	2	1	not provided (3)
-	1	-	FGFR2-related craniosynostosis (1)
-	1	-	FGFR2-related disorder (1)
-	1	-	not specified (1)

Computational Scores

Algorithm	Calibrated pred.	Score	Prediction
AlphaGenome AVI	Pathogenic	33
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.87	D
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
FATHMM_MKL	Pathogenic	0.98	D
FuncVEP CTI	Benign	0.25
GPN-Star LLR	N/A	-9.2
GPN-Star score	N/A	9.2
LIST_S2	Pathogenic	0.99	D
M_CAP	Uncertain	0.13	D
MetaRNN	Uncertain	0.66	D
MetaSVM	Uncertain	-0.13	T
Mutation Taster	N/A	13/87	disease causing (ClinVar)
MutationAssessor	Benign	1.6	L
PhyloP100	Pathogenic	10
popEVE	Benign	-3.7
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.2	D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D
Sift4G	Benign	0.67	T
Varity_R	N/A	0.70
VESM-3B	Benign	-10

Showing 28 of 28 scores

Splicing Scores

Algorithm	Calibrated pred.	Score	Prediction
Pangolin (max)	Benign	0.0
SpliceAI score (max)	Benign	0.0	Details are displayed if max score is > 0.2

Showing 2 of 2 scores

Find out detailed SpliceAI scores and Pangolin per-transcript scores at spliceailookup.broadinstitute.org

MaxEntScan Visualizer can be used to analyze the impact of this mutation on the neighboring sequence.

MaveDB functional evidence

MaveDB is a public repository of laboratory assays that test the effect of thousands of variants at once — treat this as supporting research data and interpret it with great caution; it is not a clinical classification.

No MaveDB functional evidence found for this variant.

Other links and lift over

dbSNP: rs79184941;

hg19: chr10-123279677;

COSMIC: COSV60657130;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar