NM_000141.4:c.2141A>C

FGFR2 · NP_000132.3:p.(Lys714Thr) · NM_000141.4

GRCh37: chr10:123244963 T>G · GRCh38: chr10:121485449 T>G

Gene: FGFR2 Transcript: NM_000141.4

Final call

VUS

PM2 supporting

Variant details

Gene

FGFR2

Transcript

NM_000141.4

Protein

NP_000132.3:p.(Lys714Thr)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

NM_000141.4:c.2141A>C (p.Lys714Thr) in FGFR2 is absent from all population databases (gnomAD v2.1, v4.1, gnomAD-Canada), meeting PM2 at supporting strength.

No pathogenic or benign criteria beyond PM2_Supporting are met. No functional data, case-control studies, segregation data, de novo reports, or literature evidence were identified for this specific variant.

Under generic ACMG/AMP 2015 final combination rules (PMID:25741868), a single supporting pathogenic criterion (PM2) is insufficient to reach Likely Pathogenic, and no benign criteria are met. The variant is classified as 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	NM_000141.4:c.2141A>C is a missense substitution (p.Lys714Thr), not a null variant (nonsense, frameshift, or canonical ±1,2 splice consensus). The generic PVS1 framework (PMC6185798) does not apply to missense variants outside the defined null-variant buckets.	pvs1_variant_assessment pvs1_generic_framework
PS1	Not met	No evidence of a different nucleotide change at codon 714 (AAA) producing the same missense change (p.Lys714Thr) that has been previously established as pathogenic. No ClinVar entries, literature reports, or comparator variants were identified.	clinvar
PS2	Not assessed	No de novo data available. No parental testing or family studies were identified for this variant.
PS3	Not met	No well-established functional studies demonstrating a deleterious effect for this variant were identified. OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific reviewed functional evidence. REVEL score of 0.771 does not constitute well-established functional evidence per ACMG/AMP guidelines.	oncokb revel
PS4	Not assessed	No case-control or cohort data available. The variant is absent from ClinVar, gnomAD, COSMIC, and published literature, precluding any assessment of enrichment in affected individuals.	clinvar gnomad_v2 gnomad_v4
PS5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and was not identified in any literature source.	clinvar
PM1	Not met	Residue 714 is located in the FGFR2 tyrosine kinase domain but does not fall within a statistically significant mutational hotspot per CancerHotspots.org. No gene-specific PM1 domain-level rule is established for FGFR2 under the generic ACMG/AMP framework.
PM2	Met	NM_000141.4:c.2141A>C is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0, meeting the <0.1% allele frequency threshold for PM2 in a gene where pathogenic missense variants are established.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No comparator missense variants at the same residue (Lys714) with established pathogenicity were identified in ClinVar or any other evidence source. PM5 cannot be assessed without a qualifying comparator variant previously classified as pathogenic.	pm5_candidates
PM6	Not assessed	No de novo data available. No reports of confirmed de novo occurrence for this variant were identified in ClinVar or published literature.
PP1	Not assessed	No co-segregation data available. No family studies with this variant were identified.
PP2	Not assessed	The HCI prior database does not include FGFR2 (gene_not_supported). Without a calibrated gene-specific benign missense rate, PP2 cannot be reliably assessed under generic ACMG/AMP. FGFR2 is known to harbor pathogenic missense variants in craniosynostosis syndromes, but PP2 requires quantification of the background rate of benign missense variation.
PP3	Not met	In silico predictions are conflicting and do not meet the threshold for multiple lines of computational evidence supporting a deleterious effect. REVEL score of 0.771 is above the 0.5 threshold for deleterious prediction, but BayesDel score of 0.169711 is well below the 0.27 threshold for deleterious prediction. SpliceAI predicts no splice impact (max delta score 0.01).	revel bayesdel spliceai
PP4	Not assessed	No phenotype or family history information is available for this variant. The patient's clinical presentation is unknown.
PP5	Not met	No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and was not identified in any literature source.	clinvar
BA1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. It does not meet the >1% allele frequency threshold (or >5% for BA1 standalone) in any population database.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. It does not meet the >0.3% allele frequency threshold for BS1 in any population.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on observation of this variant in healthy adults. The variant is absent from all population databases, precluding any assessment of its presence in unaffected individuals.
BS3	Not assessed	No well-established functional studies evaluating the effect of this variant were identified. OncoKB reports no variant-specific reviewed functional evidence.	oncokb
BS4	Not assessed	No segregation data available. No family studies with this variant were identified.
BP1	Not met	BP1 applies to missense variants in genes where primarily truncating variants cause disease. FGFR2 germline disorders (Apert, Crouzon, Pfeiffer syndromes) are predominantly caused by gain-of-function missense variants, and FGFR2 also has emerging associations with LOF-driven phenotypes (osteoporosis). Missense variants are a well-established disease mechanism in FGFR2, so BP1 does not apply.	pvs1_gene_context
BP2	Not assessed	No data on observation of this variant in trans with a known pathogenic dominant variant or in cis with a pathogenic recessive variant.
BP4	Not met	REVEL score of 0.771 strongly predicts a deleterious effect. Multiple lines of computational evidence do not converge on a benign prediction; BP4 requires consensus among in silico tools predicting no impact.	revel bayesdel spliceai
BP5	Not assessed	No evidence of an alternate molecular cause for the observed phenotype. No clinical or genetic data are available to assess this criterion.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	NM_000141.4:c.2141A>C is a missense variant (p.Lys714Thr), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact.	spliceai
BP3	N/A	This is a substitution variant, not an in-frame deletion/insertion; BP3 applies to in-frame indels in non-repetitive regions.
PM3	N/A	FGFR2 disorders follow autosomal dominant inheritance; PM3 (trans configuration with a pathogenic recessive variant) is not applicable.
PM4	N/A	This is a substitution variant, not a protein-length-altering in-frame deletion/insertion or stop-loss variant.

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