FGFR2

Final classification

VUS

FGFR2 c.2141A>C · p.Lys714Thr

FGFR2

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.

Gene

FGFR2

Transcript

NM_000141.4

HGVS · transcript:coding

NM_000141.4:c.2141A>C

Consequence

N/A

GRCh38

chr10:121485449 T>G

GRCh37

chr10:123244963 T>G

Basis gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS. ▾

gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.

Classification rationale

PM2 VUS

FGFR2 c.2141A>C

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.¹ 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.² 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).³

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 clinvar ↗oncokb ↗

3 generic_acmg_combination_rules

Gene diagram · NM_000141.4 · variants mapped to exon structure

FGFR2 NM_000141.4

Fetching transcript structure from UCSC…

Applied criteria · 1 applied · 21 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

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 v2.1: absent (AC=nullAN=nullAF=null).

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS1 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.

PS2 No de novo data available.

PS3 No well-established functional studies demonstrating a deleterious effect for this variant were identified.

PS4 No case-control or cohort data available.

PM1 Residue 714 is located in the FGFR2 tyrosine kinase domain but does not fall within a statistically significant mutational hotspot per CancerHotspots.org.

PM6 No de novo data available.

PP1 No co-segregation data available.

PP2 The HCI prior database does not include FGFR2 (gene_not_supported).

PP3 In silico predictions are conflicting and do not meet the threshold for multiple lines of computational evidence supporting a deleterious effect.

PP4 No phenotype or family history information is available for this variant.

PP5 No reputable source has reported this variant as pathogenic.

Benign

BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS2 No data on observation of this variant in healthy adults.

BS3 No well-established functional studies evaluating the effect of this variant were identified.

BS4 No segregation data available.

BP1 BP1 applies to missense variants in genes where primarily truncating variants cause disease.

BP2 No data on observation of this variant in trans with a known pathogenic dominant variant or in cis with a pathogenic recessive variant.

BP4 REVEL score of 0.771 strongly predicts a deleterious effect.

BP5 No evidence of an alternate molecular cause for the observed phenotype.

BP6 No reputable source has reported this variant as benign.

N/A · 6 PVS1 · PM3 · PM4 · PM5 · BP3 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.771. BayesDel score = 0.169711.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. FGFR2, a receptor tyrosine kinase, is altered by mutation, chromosomal rearrangement or amplification in various cancer types.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Re-run this variant?