Variant classification summary

NM_001174067.1:c.1731C>A

FGFR1 · NP_001167538.1:p.(Asn577Lys) · NM_001174067.1

GRCh37: chr8:38274849 G>T · GRCh38: chr8:38417331 G>T

Gene: FGFR1 Transcript: NM_001174067.1

Final call

Pathogenic

PS3 strong PS4 moderate PM1 moderate PM2 moderate PP5 supporting

Variant details

Gene

FGFR1

Transcript

NM_001174067.1

Protein

NP_001167538.1:p.(Asn577Lys)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

FGFR1 c.1731C>A (p.Asn577Lys) is a missense variant in the tyrosine kinase domain, a well-established mutational hotspot.

2

The variant is completely absent from gnomAD v2.1, v4.1, and gnomAD-Canada across all populations (PM2).

3

The variant lies within the tyrosine kinase domain hinge region, a critical functional domain and statistically significant hotspot (PM1).

4

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).

5

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).

6

ClinVar classifies this variant as Pathogenic (Variation ID 224896) based on submissions from three clinical laboratories (PP5).

7

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).

Final determination: Generic ACMG/AMP 2015 fallback rules support a Pathogenic classification based on the observed combination of very strong, strong, moderate, and supporting pathogenic criteria.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	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.
PS2	Not met	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.	clinvar
PS3	Met	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.	PMID:19224897 PMID:26920151 PMID:14602678 PMID:23817572
PS4	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada clinvar PMID:23817572 PMID:26920151 PMID:24777483 PMID:27061725
PS5	N/A	PS5 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.
PM1	Met	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.	PMID:19224897 PMID:23817572
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No 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.	pm5_candidates
PM6	Not met	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.	clinvar
PP1	Not met	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.	PMID:26920151
PP2	Not assessed	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.
PP3	Not met	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.	revel bayesdel spliceai
PP4	Not assessed	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.
PP5	Met	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.	clinvar
BA1	Not met	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%.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	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%.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	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.	gnomad_v2 gnomad_v4
BS3	Not met	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.	PMID:19224897 PMID:26920151 PMID:14602678
BS4	Not assessed	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.
BP1	Not met	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.	PMID:23817572
BP2	Not met	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.
BP4	Not met	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.	revel bayesdel spliceai
BP5	Not assessed	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.
BP6	Not met	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.	clinvar
BP7	N/A	BP7 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.

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.