Variant classification summary

NM_023110.3:c.1638C>A

FGFR1 · NP_075598.2:p.(Asn546Lys) · NM_023110.3

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

Gene: FGFR1 Transcript: NM_023110.3

Final call

VUS

PM2 supporting PP3 supporting

Variant details

Gene

FGFR1

Transcript

NM_023110.3

Protein

NP_075598.2:p.(Asn546Lys)

gnomAD AF

ClinVar

Pathogenic

OncoKB

Classification rationale

Interpretation summary

Generated evidence synthesis

1

PM2 supporting: the variant is absent from gnomAD v2.1 and v4.1.

2

PP3 supporting: REVEL 0.646 meets the adjudicated generic PP3 threshold for missense variants.

Final determination: Under generic ACMG/AMP 2015 fallback rules, PM2 supporting plus PP3 supporting does not satisfy any pathogenic, likely pathogenic, benign, or likely benign combination, so the call is VUS.

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	Not applicable: PVS1 requires a null variant (nonsense, frameshift, canonical splice, start-loss or stop-loss), and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PS1	Not assessed	Not assessed: p.Asn546Lys is reported, but no independent pathogenic nucleotide change producing the same amino-acid substitution is established.	PMID:26810070 PMID:31250151 clinvar
PS2	Not assessed	Not assessed: no proband-level parental testing confirms both maternity and paternity, and no family-history information is reported.	PMID:31250151 PMID:26810070
PS3	Not assessed	Not assessed: variant-specific reports describe FGFR1 p.N546K as activating but provide no validated functional assay results or assay-control data.	PMID:31250151 PMID:26810070
PS4	Not assessed	Not assessed: affected-cohort reports lack unaffected or population control counts, so the required PS4 odds ratio and confidence interval cannot be calculated.	PMID:31250151 PMID:26810070 gnomad_v2 gnomad_v4
PM1	Not assessed	Not assessed: p.Asn546Lys is in the kinase domain, but absence of benign variation across the relevant domain is not established.	PMID:31250151 PMID:26810070 hotspots
PM2	Met	Met at supporting: the variant is absent from gnomAD v2.1 and v4.1, below the generic PM2 threshold of <=0.0001 allele frequency.	gnomad_v2 gnomad_v4 PMID:25741868
PM3	Not assessed	Not assessed: one tumor showed N546K and R659L on different alleles, but recessive inheritance and pathogenicity of the second allele were not established.	PMID:26810070
PM4	N/A	Not applicable: PM4 requires a protein-length change, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
PM5	Not assessed	Not assessed: no different pathogenic missense substitution at FGFR1 residue 546 is established in the supplied evidence.	pm5_candidates PMID:26810070 PMID:31250151
PM6	Not assessed	Not assessed: no case-level evidence supports assumed de novo status without parental confirmation.	PMID:31250151 PMID:26810070
PP1	Not assessed	Not assessed: zero informative affected relatives or meioses are reported for co-segregation analysis.	PMID:31250151 PMID:26810070
PP2	Not assessed	Not assessed: FGFR1-specific evidence does not establish both low benign missense variation and a common missense disease mechanism.	PMID:31250151 PMID:26810070
PP3	Met	Met at supporting strength: REVEL 0.646 meets the generic PP3 threshold of >=0.644 for missense variants.	revel
PP4	Not assessed	Not assessed: the patient's phenotype and family history are not provided, so phenotype specificity for a single-gene disease cannot be judged.
PP5	Not met	Not met: exact-variant ClinVar records are pathogenic, but zero expert-panel submissions are present, so PP5's required source condition is unmet.	clinvar
BA1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, rather than having the >=0.05 allele frequency required for BA1.	gnomad_v2 gnomad_v4 PMID:25741868 clinvar
BS1	Not met	Not met: the variant is absent from gnomAD v2.1 and v4.1, so no filtering allele frequency reaches the generic BS1 threshold of >=0.01.	gnomad_v2 gnomad_v4
BS2	Not assessed	Not assessed: no healthy adult carrier or homozygote observation is provided, and the required full-penetrance early-onset context is not established.	gnomad_v2 gnomad_v4
BS3	Not assessed	Not assessed: no variant-specific validated assay demonstrates absence of damaging effects on FGFR1 protein function or splicing.
BS4	Not assessed	Not assessed: no affected relatives with variant testing are reported, so lack of segregation cannot be evaluated.	PMID:31250151 PMID:26810070
BP1	Not assessed	Not assessed: the available evidence does not establish that FGFR1 disease is primarily caused by truncating variants.	PMID:31250151 PMID:26810070
BP2	Not assessed	Not assessed: N546K was reported in trans with R659L, but R659L pathogenicity and a fully penetrant dominant disorder were not established.	PMID:26810070
BP3	N/A	Not applicable: BP3 requires an in-frame indel in a repeat region, and this is a missense variant.	pvs1_generic_framework generic_acmg_combination_rules
BP4	Not met	Not met: REVEL 0.646 exceeds the most permissive generic BP4 threshold of <=0.29 for missense variants.	revel
BP5	Not assessed	Not assessed: no case-level alternate molecular diagnosis is documented alongside this variant.
BP6	Not met	Not met: no exact-variant ClinVar expert-panel benign or likely benign classification is present; available submissions are non-expert pathogenic assertions.	clinvar
BP7	N/A	Not applicable: BP7 requires a synonymous variant, and this is a missense variant.	generic_acmg_combination_rules

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