NM_001174067.1:c.2242C>T

FGFR1 · NP_001167538.1:p.(His748Tyr) · NM_001174067.1

GRCh37: chr8:38271707 G>A · GRCh38: chr8:38414189 G>A

Gene: FGFR1 Transcript: NM_001174067.1

Final call

VUS

PM2 supporting

Variant details

Gene

FGFR1

Transcript

NM_001174067.1

Protein

NP_001167538.1:p.(His748Tyr)

gnomAD AF

ClinVar

Likely benign

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_001174067.1:c.2242C>T (p.His748Tyr) is a missense variant in exon 17 of FGFR1, encoding the tyrosine kinase domain.

This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting PM2 at a supporting level under generic ACMG/AMP thresholds.

No other pathogenic or likely pathogenic criteria were met. PVS1 is not applicable (missense, not a null variant). PS1 and PM5 could not be assessed because no pathogenic comparator missense at codon 748 was identified. PS3/BS3 were not met due to absence of variant-specific functional data; OncoKB reports 'Unknown Oncogenic Effect.' PS4 was not met because no case-control or cohort data exist. PP3/BP4 were not met due to equivocal in silico predictions (REVEL 0.648 vs. BayesDel 0.129). PP5/BP6 were not met because no reputable source has classified this specific variant, and the ClinVar match was to a different variant on a different transcript.

With only one supporting pathogenic criterion (PM2) met and no benign criteria met, the variant does not reach a classifiable tier under ACMG/AMP 2015 combination rules. The evidence is insufficient to classify this variant as pathogenic, likely pathogenic, benign, or likely benign. The variant is therefore a Variant of Uncertain Significance (VUS).

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

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	This is a missense variant (c.2242C>T, p.His748Tyr) that does not fall into any PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The variant-level assessment confirmed variant_bucket='other' and apply_generic_pvs1_framework=false per ClinGen SVI PVS1 recommendations (PMC6185798).	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence that a different missense change at the same codon (His748) has been established as pathogenic. ClinVar candidate search for same-residue comparator variants returned no candidates. The only ClinVar match was to an unrelated synonymous variant on a different transcript (NM_023110.3:c.2248C>T, p.Leu750=).	clinvar pm5_candidates
PS2	Not met	No de novo observation reported for this variant. No parental data or confirmed maternity/paternity data were available in any reviewed source.
PS3	Not met	No well-established functional studies demonstrating a deleterious effect were identified for this variant. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific curated functional evidence. No published functional studies mentioning c.2242C>T or p.His748Tyr were found in the literature sources reviewed.	oncokb
PS4	Not met	No case-control data demonstrating enrichment of this variant in affected individuals versus controls. The ClinVar record matched was for a different variant (NM_023110.3:c.2248C>T, synonymous) and is not usable. No cohort studies or case series specifically reporting NM_001174067.1:c.2242C>T were identified.	clinvar
PS5	N/A	PS5 is not a defined criterion in the standard ACMG/AMP 2015 framework (PMID:25741868). No VCEP/CSPEC-specific PS5 definition exists for FGFR1. Cannot be applied under generic ACMG/AMP rules.	generic_acmg_combination_rules
PM1	Not met	This variant (p.His748Tyr) is not located in a statistically significant mutational hotspot. Cancer Hotspots analysis confirmed the residue is not significant. COSMIC reports only 2 somatic observations. Although His748 lies within the FGFR1 tyrosine kinase domain, there is no evidence that missense variants at this specific residue are enriched in affected individuals versus the general population.
PM2	Met	This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Under generic ACMG/AMP thresholds, complete absence from population databases supports PM2 at a supporting level (allele frequency <0.1% for dominant disorders).	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue comparator missense variants were identified. Automated candidate harvesting returned zero candidates at His748 in ClinVar. PM5 requires a different pathogenic missense change at the same residue, which cannot be assessed.	pm5_candidates
PM6	Not met	No de novo observation without confirmation of paternity and maternity is reported for this variant. PM6 requires a de novo report, which is absent from all reviewed sources.
PP1	Not met	No cosegregation data are available for this variant. No family studies or pedigrees with NM_001174067.1:c.2242C>T were identified in any reviewed source.
PP2	Not met	PP2 requires a gene with a low rate of benign missense variation where missense variants are a common disease mechanism. While missense variants are a recognized mechanism in FGFR1-related disorders (Hartsfield syndrome, craniosynostosis), region-specific missense constraint data (e.g., missense Z-score or gnomAD constraint metrics for the FGFR1 kinase domain) were not available to establish a low rate of benign missense variation.
PP3	Not met	In silico predictions are equivocal. REVEL score is 0.648 (above the 0.5 midpoint, leaning pathogenic but below the typical 0.75 threshold for PP3). BayesDel score is 0.129 (below typical pathogenicity thresholds, leaning benign). SpliceAI delta score is 0.00 (no predicted splice impact). The contradictory signals from REVEL and BayesDel do not constitute multiple concordant lines of computational evidence supporting a deleterious effect.	revel bayesdel spliceai
PP4	Not met	No patient phenotype or family history data were provided. PP4 requires a phenotype or family history highly specific for a disease with a single genetic etiology. No clinical information about the proband was available in any reviewed source.
PP5	Not met	No reputable source has classified this specific variant (NM_001174067.1:c.2242C>T) as pathogenic. The ClinVar record matched by the pipeline is for a different variant (NM_023110.3:c.2248C>T, p.Leu750=, synonymous, classified as Likely benign) and is marked as not an exact match. The two GeneReviews cited by ClinVar (PMID:20301509 and PMID:20301628) do not mention this variant. No other source classifies this variant as pathogenic.	clinvar
BA1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BA1 requires an allele frequency >1% in population databases, which is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. BS1 requires an allele frequency >0.3% in population databases, which is not met.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not met	No data are available demonstrating observation of this variant in a healthy adult individual for a fully penetrant dominant disorder. BS2 cannot be applied without such evidence.
BS3	Not met	No well-established functional studies demonstrating no deleterious effect were identified for this variant. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional data. No published experimental evidence showing normal function of p.His748Tyr was found in any reviewed source.	oncokb
BS4	Not met	No cosegregation data are available to demonstrate lack of segregation with disease. BS4 requires absence of cosegregation in affected family members, which cannot be assessed without family genotype data.
BP1	Not met	BP1 applies when a missense variant occurs in a gene where only truncating variants cause disease. FGFR1-related disorders (Hartsfield syndrome, craniosynostosis, GnRH deficiency) are known to be caused by missense variants as a primary disease mechanism, including gain-of-function amino acid substitutions in the tyrosine kinase domain. BP1 is not applicable.	pvs1_gene_context
BP2	Not met	No data are available regarding observation of this variant in trans with a known pathogenic variant. BP2 requires such an observation in a fully penetrant dominant disorder, which is absent from all reviewed sources.
BP4	Not met	In silico predictions are equivocal. REVEL score is 0.648 (above 0.5, leaning pathogenic), BayesDel is 0.129 (low, leaning benign), and SpliceAI delta is 0.00 (no splice effect). The contradictory signals do not constitute multiple concordant lines of computational evidence suggesting no impact. A single low BayesDel score does not meet BP4 when contradicted by REVEL.	revel bayesdel spliceai
BP5	Not met	No evidence was found that this variant was observed in a case with an alternative molecular cause for disease. BP5 requires documentation of an alternative pathogenic variant explaining the phenotype, which is not available.
BP6	Not met	No reputable source has classified this specific variant (NM_001174067.1:c.2242C>T) as benign or likely benign. The ClinVar record matched during prefetch is for a different variant (NM_023110.3:c.2248C>T, p.Leu750=, synonymous) and is marked as not an exact match; its 'Likely benign' classification applies to that variant, not NM_001174067.1:c.2242C>T. Therefore, BP6 cannot be applied.	clinvar
BP7	N/A	This is a missense variant (c.2242C>T, p.His748Tyr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.
BP3	N/A	Skipped by pre-adjudication directive: trivially not_applicable.
PM3	N/A	Skipped by pre-adjudication directive: trivially not_applicable.
PM4	N/A	Skipped by pre-adjudication directive: trivially not_applicable.

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