10-121520163-G-C

Position:

• chr10-121520163-G-C

Variant summary

Our verdict is Pathogenic. Variant got 17 ACMG points: 17P and 0B. PM2 PM5 PP2 PP3_Strong PP5_Very_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 was absent in control chromosomes in GnomAD project. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S252F) has been classified as Likely pathogenic.

• Frequency: Genomes: not found (cov: 33)
• Consequence: FGFR2 NM_000141.5 missense
• Clinical Significance: Pathogenic criteria provided, multiple submitters, no conflicts P:39 O:1
• Conservation: PhyloP100: 9.99

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]

ACMG classification

Verdict is Pathogenic. Variant got 17 ACMG points.

• PM2: Very rare variant in population databases, with high coverage
• PM5: Other missense variant is known to change same aminoacid residue: Variant chrnull-null-null-null is described in UniProt as null.
• PP2: Missense variant in gene, where missense usually causes diseases (based on misZ statistic), FGFR2. . Gene score misZ 2.402 (greater than the threshold 3.09). Trascript score misZ 4.4365 (greater than threshold 3.09). GenCC has associacion of gene with Pfeiffer syndrome type 3, Antley-Bixler syndrome, Pfeiffer syndrome type 2, Saethre-Chotzen syndrome, Beare-Stevenson cutis gyrata syndrome, Crouzon syndrome, Jackson-Weiss syndrome, Pfeiffer syndrome type 1, LADD syndrome 1, Pfeiffer syndrome, bent bone dysplasia syndrome 1, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis, familial scaphocephaly syndrome, McGillivray type, Apert syndrome, LADD syndrome.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.965
• PP5: Variant 10-121520163-G-C is Pathogenic according to our data. Variant chr10-121520163-G-C is described in ClinVar as [Pathogenic]. Clinvar id is 13272.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars. Variant chr10-121520163-G-C is described in Lovd as [Pathogenic]. Variant chr10-121520163-G-C is described in Lovd as [Pathogenic].

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	Protein	UniProt
FGFR2	NM_022970.4	c.755C>G	p.Ser252Trp	missense_variant	7/18	ENST00000457416.7	NP_075259.4
FGFR2	NM_000141.5	c.755C>G	p.Ser252Trp	missense_variant	7/18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000457416.7	c.755C>G	p.Ser252Trp	missense_variant	7/18	1	NM_022970.4	ENSP00000410294	P4
FGFR2	ENST00000358487.10	c.755C>G	p.Ser252Trp	missense_variant	7/18	1	NM_000141.5	ENSP00000351276	A2

Frequencies

GnomAD3 genomes Cov.: 33

GnomAD3 exomes AF: 0.00000400 AC: 1 AN: 249864 Hom.: 0 AF XY: 0.00 AC XY: 0 AN XY: 135098

Gnomad AFR exome AF: 0.0000619

Gnomad AMR exome AF: 0.00

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.00

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.00

Gnomad NFE exome AF: 0.00

Gnomad OTH exome AF: 0.00

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 33

ExAC AF: 0.00000824 AC: 1

ClinVar

Significance: Pathogenic

Submissions summary: Pathogenic:39 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

Acrocephalosyndactyly type I Pathogenic:17 Other:1

Pathogenic, criteria provided, single submitter	research	Programa de Pós-Graduação em Ciências Genômicas e Biotecnologia, Universidade Católica de Brasília	Apr 01, 2015	- -
Pathogenic, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Oct 15, 2018	This variant is interpreted as Pathogenic, for Apert syndrome, autosomal dominant. The following ACMG Tag(s) were applied: PP3 => Multiple lines of computational evidence support a deleterious effect on the gene or gene product. PS3-Very Strong => 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). PM6 => Assumed de novo, but without confirmation of paternity and maternity (https://www.ncbi.nlm.nih.gov/pubmed/23546041). -
Pathogenic, criteria provided, single submitter	clinical testing	MGZ Medical Genetics Center	Jul 30, 2021	- -
Pathogenic, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Mar 18, 2019	This FGFR2 variant (rs79184941) has been identified in 71% of patients with Apert syndrome and is rare in large population datasets (gnomAD: 1/249864 total alleles; 0.0004%; no homozygotes). It has been reported as an assumed de novo variant and has been shown to segregate with disease in multiple families. Six submitters in ClinVar classify FGFR2 c.755C>G as pathogenic. Functional studies have demonstrated that this variant shows a gain-of-function effect by enhancing FGFR2 ligand binding affinity. This variant is considered pathogenic. -
Pathogenic, no assertion criteria provided	research	Institute Of Reproduction And Development, Obstetrics and Gynecology Hospital, Fudan University	Sep 16, 2021	- -
Pathogenic, no assertion criteria provided	research	Department of Genetics, Beijing BioBiggen Technology Co., Ltd.	Jun 29, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	3billion	Feb 23, 2023	The variant is observed at an extremely low frequency in the gnomAD v2.1.1 dataset (total allele frequency: <0.001%). The variant is located in a mutational hot spot and/or well-established functional domain in which established pathogenic variants have been reported. Missense changes are a common disease-causing mechanism. In silico tool predictions suggest damaging effect of the variant on gene or gene product (REVEL: 0.80; 3Cnet: 0.60). Same nucleotide change resulting in same amino acid change has been previously reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013272 / PMID: 7719344 / 3billion dataset). A different missense change at the same codon (p.Ser252Phe) has been reported as pathogenic/likely pathogenic with strong evidence (ClinVar ID: VCV000013279 / PMID: 9002682). Therefore, this variant is classified as Pathogenic according to the recommendation of ACMG/AMP guideline. -
not provided, no classification provided	literature only	GeneReviews	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Seattle Children's Hospital Molecular Genetics Laboratory, Seattle Children's Hospital	Feb 17, 2021	This is a recurrent pathogenic variant that has previously been reported in several unrelated individuals with Apert syndrome and other FGFR2-associated craniosynostosis syndromes (NBK541728). It is one of the most commonly detected variants in individuals with Apert syndrome accounting for approximately 60-70% of cases (NBK541728). This variant has been observed in one individual in the Genome Aggregation Database (1 of 249,864 alleles; v2.1.1). 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). -
Pathogenic, criteria provided, single submitter	clinical testing	Neuberg Centre For Genomic Medicine, NCGM	-	The missense variant p.S252W in FGFR2 (NM_000141.4) has been previously reported as a common mutation in Apert Syndrome (Polla D et al, 2015). Functional studies demonstrate a constituional activation of FGFR2 (Ibrahimi et al, 2001). The variant has been submitted to ClinVar as Pathogenic. The missense variant c.755C>G (p.S252W) in FGFR2 (NM_000141.5) is observed in 1/16152 (0.0062%) alleles from individuals of African background in the gnomAD dataset (Exome Aggregation Consortium et al., 2016), but was not seen in the homozygous state. In silico tools predict a damaging effect and the residue is conserved across species. For these reasons, this variant has been classified as Pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Genomic Diagnostic Laboratory, Division of Genomic Diagnostics, Children's Hospital of Philadelphia	Sep 17, 2016	- -
Pathogenic, no assertion criteria provided	literature only	OMIM	Nov 01, 2007	- -
Pathogenic, criteria provided, single submitter	clinical testing	Department of Medical Genetics, Oslo University Hospital	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Knight Diagnostic Laboratories, Oregon Health and Sciences University	Sep 20, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Genesolutions, Medical Genetics Institutes, Ho Chi Minh City, Vietnam	Jun 22, 2022	- -
Pathogenic, criteria provided, single submitter	clinical testing	Institute of Human Genetics, University of Leipzig Medical Center	Jun 07, 2024	Criteria applied: PS2,PS4,PS3_MOD,PM2_MOD,PP3 -
Pathogenic, criteria provided, single submitter	clinical testing	Laboratorio de Genetica e Diagnostico Molecular, Hospital Israelita Albert Einstein	Sep 22, 2022	ACMG classification criteria: PS3 supporting, PS4 strong, PM1 moderated, PM2 moderated, PM6 moderated, PP1 supporting, PP3 supporting -
Pathogenic, criteria provided, single submitter	clinical testing	Breakthrough Genomics, Breakthrough Genomics	Apr 11, 2022	This variant has been reported as a recurrent variant in Apert syndrome, accounting for disease in approximately 71% of affected individuals and families. It segregates with the disease in several families with multiple affected individuals [PMID: 7719344, 8651276, 25867380, 9462761, 12124745, 23546041]. Functionall studies have shown that the variant exerts a gain-of-function effect by enhancing FGFR2 binding affinity [PMID: 11390973, 22664175, 23495007, 24489893]. -

not provided Pathogenic:8

Pathogenic, criteria provided, single submitter	clinical testing	Revvity Omics, Revvity	Oct 26, 2023	- -
Pathogenic, no assertion criteria provided	clinical testing	Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC)	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	GeneDx	Feb 16, 2024	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); In silico analysis supports that this missense variant has a deleterious effect on protein structure/function; This variant is associated with the following publications: (PMID: 31879841, 28316926, 16440883, 19186770, 31387623, 34367232, 7719344, 23754559, 23495007, 22664175, 25867380, 9700203, 22105374, 10067911, 23593218, 24489893, 25297884, 9462761, 22048896, 23546041, 21154333, 25045033, 25433548, 27228464, 18215098, 28976722, 16951439, 29483804, 8651276, 30355600, 29753329, 30656008, 15282208, 30679815, 9719378, 16906598, 29037998, 30657466, 31064775, 30719288, 31502745, 30672749, 31837199, 31019026, 32954549, 10658283, 32510873, 8676562, 33937142, 35088901, 35591945, 33585639, 34958143, 34358384, 34094714, 31145570, 23519026) -
Pathogenic, no assertion criteria provided	clinical testing	Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	May 01, 2023	FGFR2: PS2, PM2, PS4:Moderate, PP3, PP4, PS3:Supporting -
Pathogenic, no assertion criteria provided	clinical testing	Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center	-	- -
Pathogenic, criteria provided, single submitter	clinical testing	Blueprint Genetics	Nov 30, 2019	- -
Pathogenic, criteria provided, single submitter	clinical testing	Clinical Genetics Laboratory, Skane University Hospital Lund	Jul 13, 2022	- -

FGFR2-related craniosynostosis Pathogenic:3

Pathogenic, criteria provided, single submitter	clinical testing	Labcorp Genetics (formerly Invitae), Labcorp	Aug 30, 2023	For these reasons, this variant has been classified as Pathogenic. Experimental studies have shown that this missense change affects FGFR2 function (PMID: 11390973, 22664175, 23495007, 24489893). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is expected to disrupt FGFR2 protein function. ClinVar contains an entry for this variant (Variation ID: 13272). This missense change has been observed in individual(s) with Apert syndrome, accounting for disease in approximately 71% of affected individuals and families (PMID: 7719344, 8651276, 9462761, 25867380). In at least one individual the variant was observed to be de novo. It has also been observed to segregate with disease in related individuals. This variant is present in population databases (rs79184941, gnomAD 0.007%). This sequence change replaces serine, which is neutral and polar, with tryptophan, which is neutral and slightly polar, at codon 252 of the FGFR2 protein (p.Ser252Trp). -
Pathogenic, criteria provided, single submitter	clinical testing	DASA	Jan 05, 2022	The c.755C>G;p.(Ser252Trp) missense variant has been observed in affected individual(s) and ClinVar contains an entry for this variant (Clinvar ID: 13272; PMID: 24489893; 25867380; 26380986; 31145570) - PS4. Well-established in vitro or in vivo functional studies support a damaging effect on the gene or gene product (PMID: 24489893) - PS3_moderate. This variant is not present in population databases (rs79184941, gnomAD; ABraOM no frequency - http://abraom.ib.usp.br/) - PM2. Missense variant in FGFR2 that has a low rate of benign missense variation and in which missense variants are a common mechanism of disease - PP2. Multiple lines of computational evidence support a deleterious effect on the gene or gene product - PP3. In summary, the currently available evidence indicates that the variant is pathogenic. -
Pathogenic, criteria provided, single submitter	research	Division of Human Genetics, National Health Laboratory Service/University of the Witwatersrand	Jul 01, 2023	- -

FGFR2-related disorder Pathogenic:2

Pathogenic, no assertion criteria provided	clinical testing	PreventionGenetics, part of Exact Sciences	Jan 13, 2024	The FGFR2 c.755C>G variant is predicted to result in the amino acid substitution p.Ser252Trp. This variant is the most common recurrent variant reported in patients with Apert syndrome (Wilkie et al. 1995. PubMed ID: 7719344, reported as c.934C>G; Passos-Bueno et al. 1998. PubMed ID: 9719378; Polla et al. 2015. PubMed ID: 26380986; Kunwar et al. 2017. PubMed ID: 28316926). The variant is observed once in population databases indicating this variant is rare. In summary, this variant is interpreted as pathogenic. -
Pathogenic, criteria provided, single submitter	clinical testing	Rady Children's Institute for Genomic Medicine, Rady Children's Hospital San Diego	-	This variant has been previously reported as a heterozygous change in individuals with Apert syndrome (PMID: 7719344, 8651276, 9462761, 25867380). It is present in the heterozygous state in the gnomAD population database at a frequency of 0.0004% (1/249864). The c.755C>G (p.Ser252Trp) variant affects a highly conserved amino acid and is predicted by multiple in silico tools to have a deleterious effect on protein function. Analysis of the parental samples was negative for the variant, indicating this variant likely occurred as a de novo event. Based on the available evidence, the c.755C>G (p.Ser252Trp) variant is classified as Pathogenic. -

Endometrial Endometrioid Adenocarcinoma, Variant with Squamous Differentiation Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Dec 26, 2014

- -

Gastric adenocarcinoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

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 Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Fulgent Genetics, Fulgent Genetics

Aug 12, 2021

- -

Uterine carcinosarcoma Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Endometrium neoplasm Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

Jul 14, 2015

- -

Pfeiffer syndrome Pathogenic:1

Pathogenic, criteria provided, single submitter

clinical testing

Center for Genomic Medicine, King Faisal Specialist Hospital and Research Center

Mar 14, 2024

- -

Malignant neoplasm of body of uterus Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 31, 2016

- -

Acrocephalosyndactyly Pathogenic:1

Likely pathogenic, no assertion criteria provided

literature only

Database of Curated Mutations (DoCM)

May 13, 2016

- -

Endometrial carcinoma Pathogenic:1

Pathogenic, no assertion criteria provided

literature only

OMIM

Nov 01, 2007

- -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
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;.;.;.;T;.;T;.;.;.;.;.
Eigen	Pathogenic	0.88
Eigen_PC	Pathogenic	0.80
FATHMM_MKL	Pathogenic	0.98	D
LIST_S2	Pathogenic	0.99	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.63	D
MutationAssessor	Pathogenic	3.4	.;.;M;.;.;M;.;M;.;M;.;M;M;.
MutationTaster	Benign	1.0	A;A;A;A;A;A;A;A;A;A;A
PrimateAI	Uncertain	0.74	T
PROVEAN	Pathogenic	-6.0	D;.;D;.;D;D;D;D;D;D;D;D;D;D
REVEL	Pathogenic	0.80
Sift	Pathogenic	0.0	D;.;D;.;D;D;D;D;D;D;D;D;D;D
Sift4G	Benign	0.18	T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		1.0	D;.;.;.;D;.;.;.;.;.;D;D;.;.
Vest4		0.81
MutPred		0.88		.;.;Loss of disorder (P = 0.0024);.;.;Loss of disorder (P = 0.0024);.;Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);.;Loss of disorder (P = 0.0024);Loss of disorder (P = 0.0024);.;
MVP		0.88
MPC		2.1
ClinPred		0.98	D
GERP RS		5.8
RBP_binding_hub_radar		0.0
RBP_regulation_power_radar		1.7
Varity_R		0.83
gMVP		0.97

Splicing

Name	Calibrated prediction	Score	Prediction
SpliceAI score (max)		0.0		Details are displayed if max score is > 0.2

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

Publications

LitVar

Other links and lift over

dbSNP: rs79184941; hg19: chr10-123279677; COSMIC: COSV60638319; COSMIC: COSV60638319;