chr10-121520163-G-C

Variant names:

• chr10-121520163-G-C
• rs79184941
• NM_022970.4:c.755C>G
• FGFR2 p.Ser252Trp

GermlineCancer (beta)

Variant summary

Our verdict is Pathogenic.

>+14 Pathogenic

-7

-6

-1

0

+5

+6

+9

+10

BenignB

Likely BenignLB

UncertainVUS

Likely PathogenicLP

PathogenicP

The variant received 17 classification points (ACMG Germline Pathogenicity v2019). PS3PM1PM2PM5PP2PP3_ModeratePP5_Strong

The NM_000141.5(FGFR2):c.755C>G (p.Ser252Trp) variant causes a missense change involving the alteration of a conserved nucleotide. 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. 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: not found (cov: 33)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:40 O:3
• Conservation: PhyloP100: 9.99
• Publications: 493 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 ACMG Germline Pathogenicity v2019

Classification was made for transcript:

Our verdict: Pathogenic. The variant received 17 points.

Apply	Criterion Code & Title / Strength	Strength	Rationale / Clinical Context
	PS3Functional studies show damaging effect		Well-established functional study supports damaging effect (PS3); 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).; SCV000925947: Functional studies have demonstrated that this variant shows a gain-of-function effect by enhancing FGFR2 ligand binding affinity.; SCV002073300: Functional studies demonstrate a constituional activation of FGFR2 (Ibrahimi et al, 2001).; SCV002525629: The c.755C>G variant is predicted to replace the serine at codon 252 with tryptophan and experimentally shown to result in a gain of function of FGFR2 (PMID: 9700203).; SCV005088771: Functionall studies have shown that the variant exerts a gain-of-function effect by enhancing FGFR2 binding affinity [PMID: 11390973, 22664175, 23495007, 24489893].; SCV000329832: "Published functional in vitro studies and transgenic mouse models demonstrate a damaging, gain-of-function effect resulting in altered receptor affinity and upregulation of FGF signaling leading to the dysregulation of genes involved in bone formation, bone mineralization and osteoclastogenesis (PMID: 23519026, 9700203, 24489893, 31064775)"; SCV000659618: Experimental studies have shown that this missense change affects FGFR2 function (PMID: 11390973, 22664175, 23495007, 24489893).; SCV002061183: "Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 24489893)"; SCV005418693: "Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product."; SCV006526673: An animal model expressing this variant exhibited phenotype(s) consistent with FGFR2-related craniosynostosis disorders (Chen, 2014; Holmes, 2012).
	PM1Mutational hot spot or critical domain		Missense neighbourhood hotspot (≥2 P/LP within ±8 AA, OR ≥ 5 vs. background) — PM1; In-domain: 0 pathogenic, 0 benign rare missense variants.; ±8 AA neighbourhood: 4 pathogenic, 0 benign (OR vs. background: 45.0).
	PM2Absent/extremely low in population databases		Absent from gnomAD (AD/XL gene) — PM2; Absent from gnomAD at well-covered site (MOI: AD+AR) (threshold 0.0001) — PM2 moderate.
	PM5Novel missense at known pathogenic residue		Different pathogenic missense at same AA residue in ClinVar (PM5); ClinVar contains a germline Pathogenic/Likely Pathogenic entry at the same amino acid position with a different amino acid change: p.S252F: Likely_pathogenic (ClinVar VariationId 13279, 1 star); Other variants at the same amino acid residue (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)
	PP2Missense in gene with low missense rate		Missense in gene constrained for missense variation where missense is common disease mechanism (PP2); Missense in a gene constrained for missense variation (gnomAD Z-score: 4.447). ClinVar shows strong pathogenic missense enrichment: 111 P/LP and 30 B/LB missense entries (ratio 3.7×).
	PP3Computational evidence supports damaging effect		Germline meta computational scorer (REVEL/MetaRNN/BayesDel) predicts damaging effect — moderate evidence (PP3); Splicing verdict: not pathogenic.; Germline computational verdict: pathogenic (Moderate).
	PP5Reputable source reports pathogenic		ClinVar 2-star pathogenic — strong (PP5); ClinVar germline classification: Pathogenic/Likely Pathogenic, 2 star(s).

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>G p.Ser252Trp	missense	Exon 7 of 18	Prot: NP_075259.4 UniProt:
	FGFR2 NM_000141.5	MANE Select	c.755C>G p.Ser252Trp	missense	Exon 7 of 18	Prot: NP_000132.3 UniProt:
	FGFR2 NM_001441087.1		c.755C>G p.Ser252Trp	missense	Exon 7 of 18	Prot: NP_001428016.1 UniProt:

FGFR2 NM_022970.4

MANE Plus Clinical

HGVSc / HGVSpc.755C>Gp.Ser252Trp

Exon rankExon 7 of 18

missense

Prot: NP_075259.4UniProt: P21802-3

FGFR2 NM_000141.5

MANE Select

HGVSc / HGVSpc.755C>Gp.Ser252Trp

Exon rankExon 7 of 18

missense

Prot: NP_000132.3UniProt: P21802-1

FGFR2 NM_001441087.1

HGVSc / HGVSpc.755C>Gp.Ser252Trp

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>G p.Ser252Trp	missense	Exon 7 of 18	Prot: ENSP00000410294.2 UniProt:
	FGFR2 ENST00000358487.10	TSL:1MANE Select	c.755C>G p.Ser252Trp	missense	Exon 7 of 18	Prot: ENSP00000351276.6 UniProt:
	FGFR2 ENST00000369056.5	TSL:1	c.755C>G p.Ser252Trp	missense	Exon 6 of 17	Prot: ENSP00000358052.1 UniProt:

FGFR2 ENST00000457416.7

TSL:1MANE Plus Clinical

HGVSc / HGVSpc.755C>Gp.Ser252Trp

Exon rankExon 7 of 18

missense

Prot: ENSP00000410294.2UniProt: P21802-3

FGFR2 ENST00000358487.10

TSL:1MANE Select

HGVSc / HGVSpc.755C>Gp.Ser252Trp

Exon rankExon 7 of 18

missense

Prot: ENSP00000351276.6UniProt: P21802-1

FGFR2 ENST00000369056.5

TSL:1

HGVSc / HGVSpc.755C>Gp.Ser252Trp

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 4 sources Large-scale international reference populations
GnomAD3 genomes	AF:	AC:	Hom:	AN:	Cov:33
GnomAD2 exomes	AF: 0.00000400	AC:1	Hom:	AN:249864	Cov:
GnomAD4 exome	AF:	AC:	Hom:	AN:	Cov:31
GnomAD4 genome	AF:	AC:	Hom:	AN:	Cov:33

Showing 4 sources

ClinVar

ClinVar submissions

Significance: Pathogenic

Revision: criteria provided, multiple submitters, no conflicts

Pathogenic	VUS	Benign	Condition
21	-	-	Acrocephalosyndactyly type I (22)
9	-	-	not provided (9)
3	-	-	FGFR2-related craniosynostosis (3)
3	-	-	FGFR2-related disorder (3)
1	-	-	Acrocephalosyndactyly type I;C0010273:Crouzon syndrome;C0024623:Gastric cancer;C0175699:Saethre-Chotzen syndrome;C0220658:Pfeiffer syndrome;C0265269:Levy-Hollister syndrome;C0795998:Jackson-Weiss syndrome;C1852406:Beare-Stevenson cutis gyrata syndrome;C1865070:Familial scaphocephaly syndrome, McGillivray type;C2936791:Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis;C3281247:Bent bone dysplasia syndrome 1 (1)
1	-	-	Endometrial carcinoma (1)
1	-	-	Inborn genetic diseases (1)
1	-	-	Pfeiffer syndrome (1)
-	-	-	Liver cancer (1)
-	-	-	Neoplasm (1)

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

Showing 29 of 29 scores

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

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: COSV60638319;

COSMIC: COSV60638319;

ACMG debug oncogenicity

ACGS debug oncogenicity

ACMG debug germline

Submit to ClinVar