10-121515260-A-G

Variant names:

• chr10-121515260-A-G
• rs121913474
• NM_000141.5:c.1144T>C

Variant summary

Our verdict is Likely pathogenic. Variant got 7 ACMG points: 7P and 0B. PM2 PP2 PP3_Moderate PP5_Moderate

The NM_000141.5(FGFR2):​c.1144T>C​(p.Cys382Arg) 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_000141.5 missense
• Clinical Significance: Pathogenic/Likely pathogenic criteria provided, multiple submitters, no conflicts P:2 O:1
• Conservation: PhyloP100: 9.23

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 Likely_pathogenic. Variant got 7 ACMG points.

• 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: 4.4365 (above the threshold of 3.09). GenCC associations: The gene is linked to 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, 0.884
• PP5: Variant 10-121515260-A-G is Pathogenic according to our data. Variant chr10-121515260-A-G is described in ClinVar as [Likely_pathogenic]. Clinvar id is 376431.Status of the report is criteria_provided_single_submitter, 1 stars.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	MANE	Protein	UniProt
FGFR2	NM_000141.5	c.1144T>C	p.Cys382Arg	missense_variant	Exon 9 of 18	ENST00000358487.10	NP_000132.3

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	Exon rank	TSL	MANE	Protein	Appris	UniProt
FGFR2	ENST00000358487.10	c.1144T>C	p.Cys382Arg	missense_variant	Exon 9 of 18	1	NM_000141.5	ENSP00000351276.6
FGFR2	ENST00000457416.7	c.1147T>C	p.Cys383Arg	missense_variant	Exon 9 of 18	1		ENSP00000410294.2
FGFR2	ENST00000369056.5	c.1147T>C	p.Cys383Arg	missense_variant	Exon 8 of 17	1		ENSP00000358052.1
FGFR2	ENST00000369058.7	c.1147T>C	p.Cys383Arg	missense_variant	Exon 9 of 17	1		ENSP00000358054.3
FGFR2	ENST00000613048.4	c.877T>C	p.Cys293Arg	missense_variant	Exon 8 of 17	5		ENSP00000484154.1
FGFR2	ENST00000369061.8	c.808T>C	p.Cys270Arg	missense_variant	Exon 6 of 15	1		ENSP00000358057.4
FGFR2	ENST00000369059.5	c.802T>C	p.Cys268Arg	missense_variant	Exon 7 of 16	5		ENSP00000358055.1
FGFR2	ENST00000360144.7	c.880T>C	p.Cys294Arg	missense_variant	Exon 8 of 17	2		ENSP00000353262.3
FGFR2	ENST00000478859.5	c.460T>C	p.Cys154Arg	missense_variant	Exon 8 of 17	1		ENSP00000474011.1
FGFR2	ENST00000604236.5	n.*191T>C		non_coding_transcript_exon_variant	Exon 8 of 17	1		ENSP00000474109.1
FGFR2	ENST00000604236.5	n.*191T>C		3_prime_UTR_variant	Exon 8 of 17	1		ENSP00000474109.1
FGFR2	ENST00000429361.5	c.-81T>C		upstream_gene_variant		5		ENSP00000404219.1

Frequencies

GnomAD3 genomes Cov.: 31

GnomAD4 exome Cov.: 31

GnomAD4 genome Cov.: 31

ClinVar

Significance: Pathogenic/Likely pathogenic

Submissions summary: Pathogenic:2 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. -

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 v4.3

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;.;.;T;.;T;.;.;.;.;.
Eigen	Uncertain	0.53
Eigen_PC	Uncertain	0.62
FATHMM_MKL	Pathogenic	0.99	D
LIST_S2	Uncertain	0.96	D;D;D;D;D;D;D;D;D;D;D;D;D;D
M_CAP	Uncertain	0.19	D
MetaRNN	Pathogenic	0.88	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	0.40	D
MutationAssessor	Uncertain	2.7	.;.;.;M;.;.;.;M;.;.;.;.;.;.
PrimateAI	Pathogenic	0.79	T
PROVEAN	Uncertain	-4.4	D;D;.;D;.;D;D;D;.;D;D;D;D;D
REVEL	Pathogenic	0.84
Sift	Uncertain	0.0020	D;D;.;D;.;D;D;D;.;D;D;D;D;D
Sift4G	Uncertain	0.050	T;T;T;T;T;T;D;T;T;D;D;D;D;.
Polyphen		0.16, 0.82, 0.42, 0.11, 0.89	.;B;.;P;.;B;.;.;.;.;B;P;.;.
Vest4		0.96
MutPred		0.71		.;.;.;Gain of sheet (P = 0.0827);.;.;.;Gain of sheet (P = 0.0827);.;.;.;.;.;.;
MVP		0.94
MPC		2.4
ClinPred		0.99	D
GERP RS		5.8
Varity_R		0.90
gMVP		0.92

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