rs79184941

Positions:

• chr10-121520163-G-A
• chr10-121520163-G-C

Variant summary

Our verdict is Uncertain significance. Variant got 1 ACMG points: 5P and 4B. PM1 PM5 PP2 BS2

The NM_000141.5(FGFR2):​c.755C>T​(p.Ser252Leu) variant causes a missense change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000403 in 1,612,936 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Conflicting classifications of pathogenicity (no stars). Another variant affecting the same amino acid position, but resulting in a different missense (i.e. S252W) has been classified as Pathogenic.

• 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:4 B:4
• 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 Uncertain_significance. Variant got 1 ACMG points.

• PM1: In a hotspot region, there are 2 aminoacids with missense pathogenic changes in the window of +-8 aminoacids around while only 0 benign, 4 uncertain in NM_000141.5
• PM5: Other missense variant is known to change same aminoacid residue: 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.
• PP2: Missense variant where missense usually causes diseases, FGFR2
• BS2: High AC in GnomAdExome4 at 63 AD gene.

Transcripts

RefSeq

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	MANE	UniProt
FGFR2	NM_022970.4	c.755C>T	p.Ser252Leu	missense_variant	7/18	ENST00000457416.7
FGFR2	NM_000141.5	c.755C>T	p.Ser252Leu	missense_variant	7/18	ENST00000358487.10

Ensembl

Gene	Transcript	HGVSc	HGVSp	Effect	#exon/exons	TSL	MANE	Appris	UniProt
FGFR2	ENST00000457416.7	c.755C>T	p.Ser252Leu	missense_variant	7/18	1	NM_022970.4	P4
FGFR2	ENST00000358487.10	c.755C>T	p.Ser252Leu	missense_variant	7/18	1	NM_000141.5	A2

Frequencies

GnomAD3 genomes AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 33

Gnomad AFR AF: 0.0000241

Gnomad AMI AF: 0.00

Gnomad AMR AF: 0.00

Gnomad ASJ AF: 0.00

Gnomad EAS AF: 0.00

Gnomad SAS AF: 0.00

Gnomad FIN AF: 0.00

Gnomad MID AF: 0.00

Gnomad NFE AF: 0.0000147

Gnomad OTH AF: 0.00

GnomAD3 exomes AF: 0.0000560 AC: 14 AN: 249864 Hom.: 0 AF XY: 0.0000666 AC XY: 9 AN XY: 135098

Gnomad AFR exome AF: 0.000124

Gnomad AMR exome AF: 0.0000581

Gnomad ASJ exome AF: 0.00

Gnomad EAS exome AF: 0.000109

Gnomad SAS exome AF: 0.00

Gnomad FIN exome AF: 0.0000467

Gnomad NFE exome AF: 0.0000620

Gnomad OTH exome AF: 0.00

GnomAD4 exome AF: 0.0000431 AC: 63 AN: 1460734 Hom.: 0 Cov.: 31 AF XY: 0.0000454 AC XY: 33 AN XY: 726542

Gnomad4 AFR exome AF: 0.0000299

Gnomad4 AMR exome AF: 0.0000224

Gnomad4 ASJ exome AF: 0.0000766

Gnomad4 EAS exome AF: 0.0000504

Gnomad4 SAS exome AF: 0.0000813

Gnomad4 FIN exome AF: 0.0000187

Gnomad4 NFE exome AF: 0.0000414

Gnomad4 OTH exome AF: 0.0000497

GnomAD4 genome AF: 0.0000131 AC: 2 AN: 152202 Hom.: 0 Cov.: 33 AF XY: 0.00 AC XY: 0 AN XY: 74346

Gnomad4 AFR AF: 0.0000241

Gnomad4 AMR AF: 0.00

Gnomad4 ASJ AF: 0.00

Gnomad4 EAS AF: 0.00

Gnomad4 SAS AF: 0.00

Gnomad4 FIN AF: 0.00

Gnomad4 NFE AF: 0.0000147

Gnomad4 OTH AF: 0.00

Bravo AF: 0.0000416

ESP6500AA AF: 0.000227 AC: 1

ESP6500EA AF: 0.00 AC: 0

ExAC AF: 0.0000577 AC: 7

ClinVar

Significance: Conflicting classifications of pathogenicity

Submissions summary: Uncertain:4 Benign:4

Revision: criteria provided, conflicting classifications

Submissions by phenotype

Crouzon syndrome Benign:3

Likely benign, criteria provided, single submitter	clinical testing	Mendelics	May 28, 2019	- -
Benign, criteria provided, single submitter	curation	SIB Swiss Institute of Bioinformatics	Apr 16, 2018	This variant is interpreted as a Benign, for Crouzon syndrome, Autosomal Dominant inheritance. The following ACMG Tag(s) were applied: BS4 => Lack of segregation in affected members of a family (PMID:9002682). BS1 => Allele frequency is greater than expected for disorder. BS2 => Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age (PMID:9002682). -
Likely benign, criteria provided, single submitter	clinical testing	Johns Hopkins Genomics, Johns Hopkins University	Jun 30, 2020	- -

not provided Uncertain:1 Benign:1

Uncertain significance, criteria provided, single submitter	clinical testing	GeneDx	Oct 14, 2022	Reported in individuals with Crouzon syndrome, inherited from apparently unaffected parents (Oldridge et al., 1997; Ohishi et al., 2017); Reported in a family where affected members had severe syndactyly without craniosynostosis and harbored a second FGFR2 variant in cis with p.(S252L) (Wilkie et al., 2002).; 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: 15282208, 15840724, 9700203, 26003532, 17621648, 9300656, 27683237, 32908727, 31348830, 9002682, 12357470, 29037998, 20301628) -
Likely benign, criteria provided, single submitter	clinical testing	CeGaT Center for Human Genetics Tuebingen	Jan 01, 2023	FGFR2: BS1 -

not specified Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Women's Health and Genetics/Laboratory Corporation of America, LabCorp

Jan 08, 2024

Variant summary: FGFR2 c.755C>T (p.Ser252Leu) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. c.755C>T has been reported in the literature in two independent families affected with Crouzon syndrome and the variant was present in both affected individuals as well as clinically normal family members (examples: Oldridge_1997, Oshini_2017). Additionally, this variant was seen in cis with a second pathogenic variant in a mother and her daughter affected with syndactyly (Wilkie_2002). At least one publication reports experimental evidence that FGFR2 mutant Ser252Leu exhibited kinetic behavior identical to wild-type (Anderson_1998). These data suggest a benign role for this variant however, other variants affecting this residue have been classified pathogenic/likely pathogenic in ClinVar (CV IDs: 13272, 13279). ClinVar contains an entry for this variant (Variation ID: 549484). The following publications have been ascertained in the context of this evaluation (PMID: 9002682, 9700203, 15282208, 11711827, 27683237, 12357470). Based on the evidence outlined above, the variant was classified as uncertain significance. -

FGFR2-related craniosynostosis Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

Invitae

Jan 28, 2023

This variant is also known as 934C>T. This missense change has been observed in individual(s) with FGFR2-related conditions (PMID: 9002682, 11711827, 27683237). This variant is present in population databases (rs79184941, gnomAD 0.01%), and has an allele count higher than expected for a pathogenic variant. This sequence change replaces serine, which is neutral and polar, with leucine, which is neutral and non-polar, at codon 252 of the FGFR2 protein (p.Ser252Leu). ClinVar contains an entry for this variant (Variation ID: 549484). In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance. This variant disrupts the p.Ser252 amino acid residue in FGFR2. Other variant(s) that disrupt this residue have been determined to be pathogenic (PMID: 7719344, 8651276, 9462761, 11390973, 22664175, 23495007, 24489893, 25867380). This suggests that this residue is clinically significant, and that variants that disrupt this residue are likely to be disease-causing. Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on FGFR2 function (PMID: 9700203). 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. -

FGFR2-related disorder Uncertain:1

Uncertain significance, criteria provided, single submitter

clinical testing

PreventionGenetics, part of Exact Sciences

Oct 04, 2022

The FGFR2 c.755C>T variant is predicted to result in the amino acid substitution p.Ser252Leu. This variant has been reported in several individuals with Crouzon syndrome, but it has also been observed in clinically normal members with the families (Oldridge et al 1997. PubMed ID: 9002682; Sakai N et al 2001. PubMed ID: 11711827; Ohishi et al. 2016. PbuMed ID: 27683237). In one study, functional analysis of this variant revealed wild-type kinetic (Anderson J et al 1998. PubMed ID: 9700203). This variant is reported in 0.012% of alleles in individuals of African descent in gnomAD (http://gnomad.broadinstitute.org/variant/10-123279677-G-A). A different substitution affecting the same amino acid (p.Ser252Trp) has been reported in association with Apert syndrome (Human Gene Mutation Database; http://www.hgmd.cf.ac.uk/). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. -

Computational scores

Source: dbNSFP v4.3

Name	Calibrated prediction	Score	Prediction
AlphaMissense	Pathogenic	0.96
BayesDel_addAF	Pathogenic	0.24	D
BayesDel_noAF	Pathogenic	0.34
CADD	Pathogenic	32
DANN	Uncertain	1.0
Eigen	Uncertain	0.32
Eigen_PC	Uncertain	0.41
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	0.13	D
MetaRNN	Uncertain	0.66	D;D;D;D;D;D;D;D;D;D;D;D;D;D
MetaSVM	Uncertain	-0.13	T
MutationTaster	Benign	1.0	D;D;D;D;D;D;D;D;D;D;D
PrimateAI	Uncertain	0.72	T
PROVEAN	Pathogenic	-5.2	D;.;D;.;D;D;D;D;D;D;D;D;D;D
REVEL	Uncertain	0.64
Sift	Uncertain	0.0020	D;.;D;.;D;T;D;D;D;D;D;D;D;D
Sift4G	Benign	0.67	T;T;T;T;T;T;T;T;T;T;T;T;T;.
Polyphen		0.51	P;.;.;.;D;.;.;.;.;.;B;P;.;.
Vest4		0.86
MVP		0.93
MPC		1.5
ClinPred		0.33	T
GERP RS		5.8
Varity_R		0.70
gMVP		0.93

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: COSV60657130; COSMIC: COSV60657130;