10-121515260-A-G

Variant names:

• chr10-121515260-A-G
• rs121913474
• NM_022970.4:c.1147T>C

Variant summary

Our verdict is Pathogenic. The variant received 15 ACMG points: 15P and 0B. PM1 PM2 PP2 PP3_Moderate PP5_Very_Strong

The NM_022970.4(FGFR2):​c.1147T>C​(p.Cys383Arg) 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 Likely pathogenic (★★).

• Frequency: Genomes: not found (cov: 31)
• Consequence: FGFR2 NM_022970.4 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:3 O:1
• Conservation: PhyloP100: 9.23
• Publications: 91 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, PanelApp Australia, G2P, Genomics England PanelApp
• Beare-Stevenson cutis gyrata syndrome

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

  Inheritance: AD Classification: DEFINITIVE, STRONG, SUPPORTIVE Submitted by: Orphanet, Ambry Genetics, ClinGen, PanelApp Australia, Genomics England PanelApp, G2P
• 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: ClinGen, PanelApp Australia, Labcorp Genetics (formerly Invitae), Ambry Genetics, Genomics England PanelApp, G2P
• Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis

  Inheritance: AD Classification: STRONG Submitted by: Genomics England PanelApp, G2P
• bent bone dysplasia syndrome 1

  Inheritance: AD Classification: STRONG, MODERATE, SUPPORTIVE Submitted by: Ambry Genetics, Labcorp Genetics (formerly Invitae), Orphanet
• familial scaphocephaly syndrome, McGillivray type

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

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

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

  Inheritance: AD Classification: SUPPORTIVE Submitted by: Orphanet
• 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

ACMG classification

Our verdict: Pathogenic. The variant received 15 ACMG points.

• PM1: In a hotspot region, there are 6 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 1 benign, 5 uncertain in NM_022970.4
• PM2: Very rare variant in population databases, with high coverage
• PP2: Missense variant in the FGFR2 gene, where missense mutations are typically associated with disease (based on misZ statistic). The gene has 114 curated pathogenic missense variants (we use a threshold of 10). The gene has 24 curated benign missense variants. Gene score misZ: 2.402 (below the threshold of 3.09). Trascript score misZ: 4.3638 (above the threshold of 3.09). GenCC associations: The gene is linked to Pfeiffer syndrome type 3, Crouzon syndrome, Apert syndrome, Antley-Bixler syndrome, Beare-Stevenson cutis gyrata syndrome, Jackson-Weiss syndrome, bent bone dysplasia syndrome 1, Pfeiffer syndrome, Saethre-Chotzen syndrome, LADD syndrome 1, familial scaphocephaly syndrome, McGillivray type, LADD syndrome, Pfeiffer syndrome type 1, Pfeiffer syndrome type 2, Antley-Bixler syndrome without genital anomalies or disordered steroidogenesis.
• PP3: MetaRNN computational evidence supports a deleterious effect, 0.884
• PP5: Variant 10-121515260-A-G is Pathogenic according to our data. Variant chr10-121515260-A-G is described in ClinVar as Pathogenic/Likely_pathogenic. ClinVar VariationId is 376431.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.

Variant Effect in Transcripts

ACMG analysis was done for transcript: NM_022970.4. You can select a different transcript below to see updated ACMG assignments.

RefSeq Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	NM_022970.4	MANE Plus Clinical	c.1147T>C	p.Cys383Arg	missense	Exon 9 of 18	NP_075259.4
	FGFR2	NM_000141.5	MANE Select	c.1144T>C	p.Cys382Arg	missense	Exon 9 of 18	NP_000132.3
	FGFR2	NM_001441087.1		c.1147T>C	p.Cys383Arg	missense	Exon 9 of 18	NP_001428016.1

Ensembl Transcripts

Selected	Gene	Transcript	Tags	HGVSc	HGVSp	Effect	Exon Rank	Protein	UniProt
	FGFR2	ENST00000457416.7	TSL:1 MANE Plus Clinical	c.1147T>C	p.Cys383Arg	missense	Exon 9 of 18	ENSP00000410294.2
	FGFR2	ENST00000358487.10	TSL:1 MANE Select	c.1144T>C	p.Cys382Arg	missense	Exon 9 of 18	ENSP00000351276.6
	FGFR2	ENST00000369056.5	TSL:1	c.1147T>C	p.Cys383Arg	missense	Exon 8 of 17	ENSP00000358052.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:3 Other:1

Revision: criteria provided, multiple submitters, no conflicts

Submissions by phenotype

not provided Pathogenic:2

Aug 16, 2023

GeneDx

Significance: Likely pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Mosaic variant present in affected tissue of patients with skin lesions in the literature (Kuentz et al., 2017; Tanaka et al., 2018; Gracis-Darder et al., 2023), including papillomatous pedunculated sebaceous nevus, non-epidermolytic keratinocytic epidermal nevus, and rounded and velvety epidermal nevus.; Mosaic variant identified in additional tumor types, including ameloblastoma, thyroid cancer, adenoid cystic carcinoma, and uterine corpus endometrial carcinoma (Brown et al., 2014; Sweeney et al., 2014; Chang et al., 2016; Chalal et al., 2018; Lu et al., 2018); Not observed at significant frequency in large population cohorts (gnomAD); 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: 29701304, 24993163, 24859340, 28757314, 36376059, 29610392, 27368441, 27095246, 26619011)

Oct 23, 2024

Clinical Genomics Laboratory, Washington University in St. Louis

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

An FGFR2 c.1144T>C (p.Cys382Arg) variant was identified at an allelic fraction consistent with somatic origin. This variant has been described in multiple individuals affected with epidermal and sebaceous nevi, and cholangiocarcinoma (Brandi G et al., PMID: 38326380; Gracia-Darder I et al., PMID: 36376059; Hempel L et al., PMID: 36188486; Kuentz P et al., PMID: 27095246; Tanaka R et al., PMID: 29701304; Theiler M et al., PMID: 33930231). This variant has been reported in the ClinVar database as likely pathogenic in a germline state by one submitter (ClinVar Variation ID: 376431), and it has also been reported in 32 cases in the cancer database COSMIC (Genomic Mutation ID: COSV60638681). The FGFR2 c.1144T>C (p.Cys382Arg) variant is absent from the general population (gnomAD v.4.1.0), indicating it is not a common variant. This variant resides within the transmembrane domain of FGFR2, which is defined as a critical functional domain (Brandi G et al., PMID: 38326380; Hempel L et al., PMID: 36188486; Nakamura I et al., PMID: 34272467; Li Y et al., PMID: 9136983). Computational predictors indicate that this variant is damaging, evidence that correlates with impact on FGFR2 function. Functional studies show that this variant leads to constitutive receptor activation, impaired differentiation, and increased transformation in two cell lines (Li Y et al., PMID: 9136983). Based on available information and an internally developed protocol informed by the ACMG/AMP guidelines for variant interpretation (Leon-Quintero FZ et al., PMID: 39434542), the FGFR2 c.1144T>C (p.Cys382Arg) variant is classified as pathogenic.

Beare-Stevenson cutis gyrata syndrome Pathogenic:1

Jan 08, 2025

Laboratoire de Génétique Moléculaire, CHU Bordeaux

Significance: Pathogenic

Review Status: criteria provided, single submitter

Collection Method: clinical testing

Adenoid cystic carcinoma Other:1

Nov 13, 2024

Genome Sciences Centre, British Columbia Cancer Agency

Significance:

Review Status: no assertion criteria provided

Collection Method: research

Computational scores

Source: dbNSFP v4.9

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	1.0
BayesDel_addAF	Pathogenic	0.43	D
BayesDel_noAF	Pathogenic	0.38
CADD	Pathogenic	29
DANN	Uncertain	1.0
DEOGEN2	Pathogenic	0.94	D
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.88	D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.7	M
PhyloP100		9.2
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-4.4	D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D
Sift4G	Uncertain	0.050	T
Polyphen		0.16	B
Vest4		0.96
MutPred		0.71		Gain of sheet (P = 0.0827)
MVP		0.94
MPC		2.4
ClinPred		0.99	D
GERP RS		5.8
PromoterAI		0.017	Neutral
Varity_R		0.90
gMVP		0.92
Mutation Taster		=0/100	disease causing (ClinVar)

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

Other links and lift over

dbSNP: rs121913474; hg19: chr10-123274774; COSMIC: COSV60638681; COSMIC: COSV60638681;