About FGFR1
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FGFR1 c.1731C>A, p.(Asn577Lys)
Classification
Pathogenic
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
Pathogenic.A pathogenic classification under the recorded framework.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 5
Benign evidence criteria: 0
Pathogenic criteria applied · 5
PS3Strong
PS3 · strong
The exact variant (FGFR1 p.Asn577Lys / p.Asn546Lys on canonical transcript NM_023110.3) has been directly tested in multiple independent functional studies demonstrating unequivocal gain-of-function effects. PMID:19224897 (Lew et al., 2009) showed the N546K mutant increases FGFR1 autophosphorylation rate 25-fold, disrupts ordered autophosphorylation kinetics, and induces morphological transformation in Rat-1 cells. PMID:26920151 (Rivera et al., 2016) demonstrated constitutive FGFR1 phosphorylation, elevated phospho-ERK under both starvation and reactivation conditions, and oncogene-induced senescence in HEK293 cells. PMID:14602678 (Liu et al., 2003) showed N546K induces ectopic Gbx2, Fgf8, and Spry1 expression and midbrain enlargement in chick embryo electroporation assays. Three independent publications provide direct variant-specific experimental evidence of gain-of-function, meeting PS3 at strong strength.
PS4Moderate
PS4 · moderate
This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations, and has been reported in multiple unrelated probands with consistent phenotypes. At least five independent publications describe this variant in affected individuals: mosaic activating mutation causing encephalocraniocutaneous lipomatosis (PMID:26942290), recurrent somatic mutation in pilocytic astrocytoma (PMID:23817572, n=5+), DNET (PMID:26920151), papillary glioneuronal tumor (PMID:24777483), diffuse leptomeningeal tumor (PMID:27061725), and rosette-forming glioneuronal tumor (PMID:27626068). ClinVar reports classification as Pathogenic by three clinical laboratories (ClinVar ID 224896). The complete absence from population databases combined with multiple proband observations supports PS4 at moderate strength.
PM1Moderate
PM1 · moderate
The variant alters residue Asn577 (Asn546 on canonical transcript NM_023110.3), which lies within the tyrosine kinase domain of FGFR1. This position is a well-established mutational hotspot in the kinase hinge region. Cancerhotspots.org identifies this residue as a statistically significant hotspot. The tyrosine kinase domain is a critical functional domain; mutations at this residue (N546K) have been shown to alter kinase autoinhibition and increase catalytic activity (PMID:19224897). Multiple independent tumor types harbor mutations at this exact codon (PMID:23817572, PMID:26920151). PM1 is met at moderate strength.
PM2Moderate
PM2 · moderate
This variant is completely absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes) across all populations. Under generic ACMG/AMP 2015 rules, absence from large population databases supports PM2 at moderate strength for a rare disease variant.
PP5Supporting
PP5 · supporting
ClinVar reports this variant as Pathogenic (Variation ID 224896) by three clinical laboratories. Although the aggregate review status is 'criteria provided, single submitter' (1-star), the variant is classified as Pathogenic by multiple reputable clinical laboratories, which meets the generic ACMG/AMP PP5 criterion: a reputable source reports the variant as pathogenic but the evidence is not independently evaluated. Applied at supporting strength.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PS3 strong, PS4 moderate, PM1 moderate, PM2 moderate, PP5 supporting; combination = 1 strong + 3 moderate + 1 supporting, which maps to Pathogenic.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
3 reported laboratory submissions
3 Pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
Functional evidence
Statement recorded
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
COSMIC
Cancer Hotspots
Somatic evidence
49 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV58329537, n = 49 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 5 met · 13 not met · 4 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
FGFR1 c.1731C>A (p.Asn577Lys) is a missense variant in the tyrosine kinase domain, a well-established mutational hotspot.
The variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations (PM2).
The variant lies within the tyrosine kinase domain hinge region, a critical functional domain and statistically significant hotspot (PM1).
Multiple independent functional studies demonstrate that this variant causes gain-of-function effects: 25-fold increase in FGFR1 autophosphorylation rate, disrupted ordered phosphorylation, elevated MAPK/ERK signaling, and cellular transformation (PS3_strong).
The variant has been reported in multiple unrelated probands with consistent phenotypes including encephalocraniocutaneous lipomatosis, pilocytic astrocytoma, dysembryoplastic neuroepithelial tumor, and other glioneuronal tumors (PS4_moderate).
ClinVar classifies this variant as Pathogenic (Variation ID 224896) based on submissions from three clinical laboratories (PP5).
No benign criteria are met; functional studies show gain-of-function effects that contradict BS3 and BP4, the variant is absent from population databases (contradicting BA1, BS1, BS2), and ClinVar reports the variant as Pathogenic (contradicting BP6).
No criteria match.
Met · 5
PS3 StrongThe exact variant (FGFR1 p.Asn577Lys / p.Asn546Lys on canonical transcript NM_023110.3) has been directly tested in multiple independent functional studies demonstrating unequivocal gain-of-function effects. PMID:19224897 (Lew et al., 2009) showed the N546K mutant increases FGFR1 autophosphorylation rate 25-fold, disrupts ordered autophosphorylation kinetics, and induces morphological transformation in Rat-1 cells. PMID:26920151 (Rivera et al., 2016) demonstrated constitutive FGFR1 phosphorylation, elevated phospho-ERK under both starvation and reactivation conditions, and oncogene-induced senescence in HEK293 cells. PMID:14602678 (Liu et al., 2003) showed N546K induces ectopic Gbx2, Fgf8, and Spry1 expression and midbrain enlargement in chick embryo electroporation assays. Three independent publications provide direct variant-specific experimental evidence of gain-of-function, meeting PS3 at strong strength. Details ▾Hide ▴
Evidence considered
- FGFR1 N546K kinase domain: 25x increase in autophosphorylation rate
- disrupted ordered phosphorylation
- Rat-1 cell transformation (PMID:19224897).
- FGFR1 N546K in HEK293: constitutive FGFR1 phosphorylation
- elevated pERK under starvation and reactivation
- oncogene-induced senescence (PMID:26920151).
- FGFR1 N546K chick electroporation: induced Gbx2
- Fgf8
- Spry1 expression and midbrain enlargement (PMID:14602678).
- Recurrent N546K in pilocytic astrocytoma with phospho-FGFR1 positivity by IHC (PMID:23817572).
Sources
PS4 ModerateThis variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations, and has been reported in multiple unrelated probands with consistent phenotypes. At least five independent publications describe this variant in affected individuals: mosaic activating mutation causing encephalocraniocutaneous lipomatosis (PMID:26942290), recurrent somatic mutation in pilocytic astrocytoma (PMID:23817572, n=5+), DNET (PMID:26920151), papillary glioneuronal tumor (PMID:24777483), diffuse leptomeningeal tumor (PMID:27061725), and rosette-forming glioneuronal tumor (PMID:27626068). ClinVar reports classification as Pathogenic by three clinical laboratories (ClinVar ID 224896). The complete absence from population databases combined with multiple proband observations supports PS4 at moderate strength. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada (all populations).
- Reported in multiple unrelated probands with ECCL (PMID:26942290)
- pilocytic astrocytoma (PMID:23817572)
- DNET (PMID:26920151)
- PGNT (PMID:24777483)
- DL-GNT (PMID:27061725)
- and RGNT (PMID:27626068).
- Classified as Pathogenic by 3 clinical laboratories in ClinVar (ID 224896).
Sources
PM1 ModerateThe variant alters residue Asn577 (Asn546 on canonical transcript NM_023110.3), which lies within the tyrosine kinase domain of FGFR1. This position is a well-established mutational hotspot in the kinase hinge region. Cancerhotspots.org identifies this residue as a statistically significant hotspot. The tyrosine kinase domain is a critical functional domain; mutations at this residue (N546K) have been shown to alter kinase autoinhibition and increase catalytic activity (PMID:19224897). Multiple independent tumor types harbor mutations at this exact codon (PMID:23817572, PMID:26920151). PM1 is met at moderate strength. Details ▾Hide ▴
Evidence considered
- Residue located in the tyrosine kinase domain hinge region
- a critical functional domain.
- Cancerhotspots.org identifies this position as a statistically significant hotspot.
- N546K disrupts kinase autoinhibition
- increasing autophosphorylation rate 25-fold (PMID:19224897).
Sources
PM2 ModerateThis variant is completely absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes) across all populations. Under generic ACMG/AMP 2015 rules, absence from large population databases supports PM2 at moderate strength for a rare disease variant. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (allele count = 0).
- Absent from gnomAD v4.1 (allele count = 0).
- Absent from gnomAD-Canada v1.0 (allele count = 0).
Sources
PP5 SupportingClinVar reports this variant as Pathogenic (Variation ID 224896) by three clinical laboratories. Although the aggregate review status is 'criteria provided, single submitter' (1-star), the variant is classified as Pathogenic by multiple reputable clinical laboratories, which meets the generic ACMG/AMP PP5 criterion: a reputable source reports the variant as pathogenic but the evidence is not independently evaluated. Applied at supporting strength. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 224896 classified as Pathogenic by 3 clinical laboratories.
- Multiple submissions with consistent pathogenic interpretation.
Sources
Not met · 13 · evaluated, threshold not reached
PS1 PS1 requires the same amino acid change (p.Asn577Lys) resulting from a different nucleotide change to have been previously established as pathogenic. No evidence of an alternative nucleotide substitution (e.g., c.1731C>G) producing p.Asn577Lys and classified as pathogenic was identified in ClinVar, the literature, or any database. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change producing the same amino acid substitution was identified as pathogenic.
PS2 No confirmed de novo occurrence with both maternity and paternity confirmed was identified. ClinVar submissions are predominantly somatic origin or of unknown origin. The variant has been reported as mosaic in encephalocraniocutaneous lipomatosis (PMID:26942290), but mosaic postzygotic events do not satisfy PS2 requirements for confirmed germline de novo status. Details ▾Hide ▴
Evidence considered
- No confirmed germline de novo reports with parental confirmation available.
Sources
PM6 No confirmed de novo occurrence with parental confirmation was identified. The variant has been reported as mosaic (postzygotic) in encephalocraniocutaneous lipomatosis (PMID:26942290), but mosaic events do not satisfy PM6 requirements for confirmed germline de novo status. ClinVar submissions are predominantly of somatic or unknown origin. Details ▾Hide ▴
Evidence considered
- Mosaic occurrence reported but no confirmed germline de novo with parental testing.
Still missing
- Confirmation of de novo status with parental testing would be needed to apply PM6.
Sources
PP1 No co-segregation data in affected families was identified. The familial DNET study (PMID:26920151) describes a germline FGFR1 p.R661P variant segregating with disease, not c.1731C>A/p.Asn577Lys; this variant was somatic in the affected family members. No other family studies with segregation analysis for this variant were found. Details ▾Hide ▴
Evidence considered
- No co-segregation data for this variant in families identified.
Sources
PP3 In silico evidence is mixed and does not provide multiple lines of computational support for a deleterious effect. REVEL score is 0.646 (marginally above the 0.5 threshold but below the 0.7 stringent cutoff). BayesDel score is -0.072 (below the damaging threshold). SpliceAI max delta score is 0.00 (no predicted splicing impact). HCI prior score not available for this gene. The divergent in silico predictions do not meet the requirement for multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL = 0.646 (marginally above 0.5 damaging threshold).
- BayesDel = -0.072 (below damaging threshold
- does not support pathogenicity).
- SpliceAI max delta = 0.00 (no predicted splicing impact).
Sources
BA1 This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, which does not exceed the BA1 threshold of >1%. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.0 in all gnomAD populations.
Sources
BS1 This variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, which does not exceed the BS1 threshold of >0.3%. Details ▾Hide ▴
Evidence considered
- Allele frequency = 0.0 in all gnomAD populations.
Sources
BS2 The variant is absent from all population databases, and there is no evidence of healthy adult carriers. BS2 requires observation in healthy adults with full penetrance expected at an early age. No such observations exist for this variant. Details ▾Hide ▴
Evidence considered
- No observations in healthy controls
- absent from all population databases.
Sources
BS3 Well-established functional studies show a gain-of-function deleterious effect, not a benign effect. Multiple independent publications demonstrate that this variant increases FGFR1 kinase activity, disrupts ordered autophosphorylation, elevates downstream MAPK/ERK signaling, and induces cellular transformation (PMID:19224897, PMID:26920151, PMID:14602678). These findings are diametrically opposed to the requirements of BS3, which requires functional evidence showing no deleterious effect. Details ▾Hide ▴
Evidence considered
- Functional studies demonstrate gain-of-function: increased kinase activity
- elevated pERK
- cellular transformation (PMID:19224897
- PMID:26920151).
Sources
BP1 BP1 applies to missense variants in genes where only truncating variants cause disease. FGFR1 missense variants, including this exact residue (N546K/N577K), are a well-established disease mechanism across multiple phenotypes (ECCL, pilocytic astrocytoma, DNET, PGNT, Hartsfield syndrome). BP1 does not apply. Details ▾Hide ▴
Evidence considered
- FGFR1 missense variants are an established disease mechanism
- this is not a gene where only truncating variants cause disease.
Sources
BP2 BP2 requires observation of the variant in trans with a known pathogenic variant for a fully penetrant dominant disorder. No such observation exists for this variant. FGFR1-related disorders include both autosomal dominant and autosomal recessive inheritance patterns, but no evidence of in trans configuration with another pathogenic FGFR1 variant in an unaffected individual was identified. Details ▾Hide ▴
Evidence considered
- No observation of this variant in trans with a pathogenic variant in an unaffected individual.
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. The REVEL score is 0.646, which is above the 0.5 threshold and suggests a damaging effect. BayesDel score (-0.072) is negative but does not provide strong evidence of no impact. SpliceAI predicts no splicing impact, but this alone does not constitute multiple lines of evidence suggesting no impact. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL = 0.646 (suggests damaging
- contradicts BP4).
- BayesDel = -0.072 (not strongly benign).
- SpliceAI max delta = 0.00.
Sources
BP6 BP6 requires a reputable source to report the variant as benign. ClinVar reports this variant as Pathogenic (Variation ID 224896) by three clinical laboratories. No reputable source classifies this variant as benign or likely benign. BP6 is not met. Details ▾Hide ▴
Not assessed · 4 · no assessment recorded
PP2 PP2 applies to missense variants in genes where missense variants are a common mechanism of disease and the gene has a low rate of benign missense variation. FGFR1 exhibits both gain-of-function and loss-of-function mechanisms depending on variant type and location. Constraint metrics (Z-score, missense constraint) were not available in the prefetch data for this transcript. Without quantitative constraint data, PP2 cannot be confidently assessed. Details ▾Hide ▴
Evidence considered
- Constraint metrics not available
- FGFR1 has mixed LOF/GOF disease mechanisms.
Still missing
- Missense constraint metrics (gnomAD Z-score
- LOEUF) needed for PP2 assessment.
PP4 PP4 requires the patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The specific phenotype of the proband under evaluation is not available in the case materials. While FGFR1-related disorders (ECCL, Hartsfield syndrome) have distinctive phenotypes, PP4 cannot be applied without the patient's clinical details. Details ▾Hide ▴
Evidence considered
- Patient phenotype information not provided in case materials.
Still missing
- Patient clinical phenotype details needed for PP4 assessment.
BS4 No co-segregation or lack-of-segregation data in affected families was identified for this variant. BS4 requires evidence that the variant does not segregate with disease, which cannot be evaluated without family studies. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- Family segregation data needed for BS4 assessment.
BP5 BP5 requires the variant to be found in a case with an alternate molecular basis for disease. The patient's full genetic testing results are not available, so it is unknown whether another pathogenic variant was identified that could explain the phenotype. Details ▾Hide ▴
Evidence considered
- Patient's alternate molecular findings not available.
Still missing
- Full genetic testing results needed for BP5 assessment.
Not applicable · 4· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001174067.1:c.1731C>A is a missense variant (p.Asn577Lys). It does not fall into the default generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. The variant bucket is 'other' per the PVS1 variant assessment; apply_generic_pvs1_framework is false. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a null variant eligible for PVS1 under generic ACMG/ClinGen SVI framework (PMC6185798).
Sources
PM5 N/ANo same-residue comparator variants with a different amino acid change classified as pathogenic were identified at residue Asn577. The PM5 candidates search found zero candidates and recommended not_applicable. Details ▾Hide ▴
Evidence considered
- No same-residue comparator variants at p.Asn577 identified.
Sources
pm5_candidates
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_001174067.1:c.1731C>A is a missense variant (p.Asn577Lys), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous. BP7 only applies to synonymous variants.
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion. In some expanded frameworks, PS5 refers to a variant found in trans with a pathogenic variant for a recessive disorder, or as a composite criterion. FGFR1-related disorders include both autosomal dominant (heterozygous gain-of-function) and autosomal recessive (biallelic loss-of-function) inheritance patterns. This missense gain-of-function variant (N577K) is not evaluated in a biallelic context, and no evidence supports any alternative PS5 interpretation. Marked not_applicable under generic ACMG framework. Details ▾Hide ▴
Evidence considered
- PS5 is not a standard ACMG/AMP 2015 criterion
- no applicable evidence identified.
Identifiers
- Gene
- FGFR1
- Transcript
- NM_001174067.1
- Coding (HGVS c.)
- NM_001174067.1:c.1731C>A
- Protein (HGVS p.)
- NP_001167538.1:p.(Asn577Lys)
- GRCh38
- chr8:38417331 G>T
- GRCh37
- chr8:38274849 G>T
- ClinVar
- 224896
- COSMIC
- COSV58329537
Gene diagram
Every interpreted variant in FGFR1, mapped onto the exon structure of NM_001174067.1. Select a row to find it on the plot.
FGFR1NM_001174067.1
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in FGFR1
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.646
- BayesDel
- -0.072
How the predictions were used
PP3 In silico evidence is mixed and does not provide multiple lines of computational support for a deleterious effect. REVEL score is 0.646 (marginally above the 0.5 threshold but below the 0.7 stringent cutoff). BayesDel score is -0.072 (below the damaging threshold). SpliceAI max delta score is 0.00 (no predicted splicing impact). HCI prior score not available for this gene. The divergent in silico predictions do not meet the requirement for multiple lines of computational evidence supporting a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL = 0.646 (marginally above 0.5 damaging threshold).
- BayesDel = -0.072 (below damaging threshold
- does not support pathogenicity).
- SpliceAI max delta = 0.00 (no predicted splicing impact).
Sources
BP4 BP4 requires multiple lines of computational evidence suggesting no impact on gene or gene product. The REVEL score is 0.646, which is above the 0.5 threshold and suggests a damaging effect. BayesDel score (-0.072) is negative but does not provide strong evidence of no impact. SpliceAI predicts no splicing impact, but this alone does not constitute multiple lines of evidence suggesting no impact. BP4 is not met. Details ▾Hide ▴
Evidence considered
- REVEL = 0.646 (suggests damaging
- contradicts BP4).
- BayesDel = -0.072 (not strongly benign).
- SpliceAI max delta = 0.00.
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splicing impact. NM_001174067.1:c.1731C>A is a missense variant (p.Asn577Lys), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense
- not synonymous. BP7 only applies to synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.646. BayesDel score = -0.0722477.
6 paper records listed. 6 cited in the classification.
Cited in the classification
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PMID 14602678 ↗FGF17b and FGF18 have different midbrain regulatory properties from FGF8b or activated FGF receptors.Liu A et al. · 2003 DecFGFR1 N546K (equivalent to N577K) was directly tested via chick embryo electroporation. The mutant induced ectopic expression of Gbx2, Fgf8, and Spry1 in scattered midbrain cells, and produced an enlarged midbrain phenotype at later stages. Gene expression changes were similar to those induced by activated FGFR2, consistent with gain-of-function.→ PS3 Names this variant
Source detail
Two mutant forms of human FGFR1, N546K and K656E (M. Mohammadi, unpublished), as well as one mutant form of human FGFR2, C342Y, were used in this study.
Location Results, paragraphs on activated FGFRs; Table 1; Figure 5
Context Chick in ovo electroporation, stage 9-12 embryos, midbrain/caudal forebrain; mouse brain explant culture
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PMID 19224897 ↗The precise sequence of FGF receptor autophosphorylation is kinetically driven and is disrupted by oncogenic mutations.Lew ED et al. · 2009 Feb 17FGFR1 N546K was directly tested in the isolated kinase domain. The mutation increased the rate of first-stage autophosphorylation 25-fold (0.25 s-1 vs 0.009 s-1 wild-type) and disrupted the ordered autophosphorylation sequence, producing heterogeneous phosphorylation. Stable expression of full-length FGFR1 N546K in Rat-1 cells induced morphological transformation characterized by decreased cell spreading and adhesion.→ PS3 → PM1 Names this variant
Source detail
one of these mutations, N546K, resides in the vicinity of the hinge region between the N and C lobes... Formation of the monophosphorylated species (0P to 1P) was 25 times faster with the N546K mutant (0.25 s-1) than with wild-type FGFR1 kinase (0.009 s-1)
Location Results (sections on glioblastoma FGFR1 mutant); Figure 5; Discussion paragraph 4
Context In vitro kinase assay with purified FGFR1 kinase domain; stable expression in Rat-1 fibroblasts
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PMID 23817572 ↗Recurrent somatic alterations of FGFR1 and NTRK2 in pilocytic astrocytoma.Jones DT et al. · 2013 AugFGFR1 N546K identified as a recurrent somatic hotspot mutation in pilocytic astrocytoma. Found in 5 tumors in the discovery cohort and confirmed in 9 additional cases in the validation cohort. All FGFR1-mutant tumors were extra-cerebellar and midline. Immunohistochemistry showed strong phospho-FGFR1 positivity in all N546K-mutant tumors. The mutation was mutually exclusive with other MAPK pathway alterations (BRAF, KRAS, NF1).→ PS4 → PM1 Names this variant
Source detail
mutation of two hotspot residues (N546 and K656) in the kinase domain of FGFR1, was seen in five tumors... The N546K mutation alters FGFR1 auto-phosphorylation, resulting in increased kinase activity and transforming potential
Location Results (FGFR1 section); Supplementary Table 3; Figure 3a
Context Whole-genome sequencing of 96 pilocytic astrocytomas; targeted validation in 45 additional cases; immunohistochemistry for phospho-FGFR1 and phospho-ERK
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PMID 24777483 ↗FGFR1 N546K mutation in a case of papillary glioneuronal tumor (PGNT).FGFR1 N546K mutation identified in a papillary glioneuronal tumor (PGNT) in a 33-year-old male. This was the first report of FGFR1 N546K in a glioneuronal tumor. Tumor cells were positive for phospho-ERK and focally positive for phospho-FGFR1 by immunohistochemistry.→ PS4 Names this variant
Source detail
The pyrosequencing analysis of the two hotspots of the FGFR1 gene revealed at codon 546 an AAC->AAA substitution corresponding to an Asn->Lys mutation
Location Results; Figure 1g, 1h
Context Pyrosequencing of FFPE tumor tissue; immunohistochemistry for phospho-FGFR1 and phospho-ERK
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PMID 26920151 ↗Germline and somatic FGFR1 abnormalities in dysembryoplastic neuroepithelial tumors.FGFR1 N546K (c.1638C>A) identified as a somatic hotspot mutation in dysembryoplastic neuroepithelial tumors (DNET). Multiple sporadic DNETs harbored this mutation. Functional characterization in HEK293 cells showed that N546K causes constitutive FGFR1 phosphorylation, significantly elevated phospho-ERK under both serum starvation and reactivation conditions, and oncogene-induced senescence by beta-galactosidase assay. In silico modeling predicted the mutation favors the active kinase conformation.→ PS3 → PS4 Names this variant
Source detail
Immunoblotting of phospho-FGFR1 revealed constitutive phosphorylation of FGFR1 in the p.N546K mutant under normal growth conditions... p.N546K showed higher levels of phospho-ERK than cells overexpressing either FGFR1-wild type or p.R661P (both p < 0.05)
Location Results (Molecular Investigation, MAPK-ERK signaling); Figure 4; Table 2
Context HEK293 cells stably expressing FGFR1 N546K; flow cytometry for phospho-ERK; western blot; beta-galactosidase senescence assay
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PMID 27061725 ↗FGFR1 N546K and H3F3A K27M mutations in a diffuse leptomeningeal tumour with glial and neuronal markers.FGFR1 N546K identified in a diffuse leptomeningeal tumor with glial and neuronal markers in a 15-year-old male, co-occurring with H3F3A K27M. The tumor showed elevated Ki-67 (10-15%) and aggressive clinical course. Authors note N546K has been reported in pilocytic astrocytoma, DNET, and other glioneuronal tumors.→ PS4 Names this variant
Source detail
Genomic alterations detected by tumor genome profiling identified perturbations in the FGFR1... FGFR1 (N546K)
Location Case Report; Discussion; Table 1
Context Foundation Medicine tumor genome profiling (315-gene panel); immunohistochemistry
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
3 Pathogenic
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/224896/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/8-38274849-G-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr8-38417331-G-T?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/8-38417331-G-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001174067.1%3Ac.1…
- OncoKB ↗www.oncokb.org/gene/FGFR1/N577K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=155848471
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Pathogenic (3 clinical laboratories). (ClinVarID = 224896)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.646. BayesDel score = -0.0722477.
Functional
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.
Somatic
This variant lies in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV58329537, n = 49 times).
Cancer Hotspots
This variant lies in a statistically significant hotspot.