About FGFR2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FGFR2 c.2141A>C, p.(Lys714Thr)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
29 criteria with recorded statuses: 1 met · 11 not met · 11 not assessed · 6 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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).
No criteria match.
Met · 1
PM2 SupportingNM_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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AC=null
- AN=null
- AF=null).
- gnomAD v4.1: absent (AC=null
- gnomAD-Canada v1.0: absent (AC=0
- AN=0
- AF=0.0).
Sources
Not met · 11 · evaluated, threshold not reached
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. No ClinVar entries, literature reports, or comparator variants were identified. Details ▾Hide ▴
Evidence considered
- ClinVar is empty for this variant
- no alternate nucleotide changes at codon 714 identified in any evidence source.
Still missing
- No comparator nucleotide changes at codon 714 available for assessment.
Sources
PS3 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. Details ▾Hide ▴
Evidence considered
- OncoKB classification: Unknown Oncogenic Effect
- no variant-specific functional studies curated.
- REVEL score: 0.771 (suggestive but insufficient alone for PS3).
Still missing
- No published functional studies evaluating the impact of p.Lys714Thr on FGFR2 signaling
- kinase activity
- or downstream pathways.
Sources
oncokb ↗revel
PM1 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. Details ▾Hide ▴
Evidence considered
- CancerHotspots.org: residue Lys714 is not a statistically significant hotspot (exact_variant_listed: no
- residue_significant: false).
Still missing
- No FGFR2-specific PM1 domain map available to assess functional domain-level enrichment.
PP3 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). Details ▾Hide ▴
Evidence considered
- REVEL: 0.771 (deleterious).
- BayesDel: 0.169711 (benign).
- SpliceAI max delta: 0.01 (no predicted splice impact).
Sources
PP5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and was not identified in any literature source. Details ▾Hide ▴
Evidence considered
- ClinVar: no entries
- no expert panel classifications.
- Literature: no PMIDs found across evidence sources.
Sources
BA1 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. Details ▾Hide ▴
Evidence considered
- Allele frequency: 0.0 across all queried population databases.
Sources
BS1 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. Details ▾Hide ▴
Evidence considered
- Allele frequency: 0.0 across all queried population databases.
Sources
BP1 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. Details ▾Hide ▴
Evidence considered
- FGFR2 germline disease mechanism includes both missense (gain-of-function
- craniosynostosis) and emerging LOF phenotypes.
- Missense is a known pathogenic mechanism
- BP1 is therefore not applicable.
Sources
pvs1_gene_context
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.771 (deleterious
- conflicts with BP4).
- BayesDel: 0.169711 (benign).
- SpliceAI max delta: 0.01 (neutral).
- No consensus for benign prediction.
Sources
BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴
PS5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and was not identified in any literature source. Details ▾Hide ▴
Evidence considered
- ClinVar: variant absent
- no submitter classifications available.
- Literature: no PMIDs identified across evidence sources.
Sources
Not assessed · 11 · no assessment recorded
PS2 No de novo data available. No parental testing or family studies were identified for this variant. Details ▾Hide ▴
Still missing
- De novo status cannot be evaluated without parental genotype data.
PS4 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. Details ▾Hide ▴
Evidence considered
- Variant absent from all queried databases
- no affected-vs-control comparison possible.
Still missing
- No case reports or cohort studies identified for this variant.
Sources
PM6 No de novo data available. No reports of confirmed de novo occurrence for this variant were identified in ClinVar or published literature. Details ▾Hide ▴
Still missing
- De novo status cannot be evaluated without parental genotype data.
PP1 No co-segregation data available. No family studies with this variant were identified. Details ▾Hide ▴
Still missing
- No family pedigrees or segregation data available.
PP2 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. Details ▾Hide ▴
Evidence considered
- HCI prior: not found for FGFR2 (gene_not_supported).
- FGFR2 germline disorders (Apert
- Crouzon
- Pfeiffer) are missense-driven
- but the gene-level benign missense constraint is not quantified.
Still missing
- No gene-specific PP2 calibration available for FGFR2.
PP4 No phenotype or family history information is available for this variant. The patient's clinical presentation is unknown. Details ▾Hide ▴
Still missing
- No clinical phenotype data provided.
BS2 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. Details ▾Hide ▴
Still missing
- No data on observation in healthy adult controls.
BS3 No well-established functional studies evaluating the effect of this variant were identified. OncoKB reports no variant-specific reviewed functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional data curated.
Still missing
- No published functional studies available for p.Lys714Thr.
Sources
BS4 No segregation data available. No family studies with this variant were identified. Details ▾Hide ▴
Still missing
- No family pedigrees or segregation data available.
BP2 No data on observation of this variant in trans with a known pathogenic dominant variant or in cis with a pathogenic recessive variant. Details ▾Hide ▴
Still missing
- No phasing or co-occurrence data available.
BP5 No evidence of an alternate molecular cause for the observed phenotype. No clinical or genetic data are available to assess this criterion. Details ▾Hide ▴
Still missing
- No alternate molecular diagnosis identified or excluded.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Variant classified as 'other' by PVS1 bucket assignment
- canonical splice consensus not involved
- apply_generic_pvs1_framework is false.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/AFGFR2 disorders follow autosomal dominant inheritance; PM3 (trans configuration with a pathogenic recessive variant) is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AThis is a substitution variant, not a protein-length-altering in-frame deletion/insertion or stop-loss variant. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo 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. Details ▾Hide ▴
Evidence considered
- PM5 candidate pipeline: total_candidates_seen=0
- same_residue_candidates=0.
- Recommendation: not_applicable — unable to confirm classic same-residue PM5 semantics.
Still missing
- No pathogenic missense variants at Lys714 identified to serve as PM5 comparators.
Sources
pm5_candidates
BP3 N/AThis is a substitution variant, not an in-frame deletion/insertion; BP3 applies to in-frame indels in non-repetitive regions. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Variant type: missense substitution
- BP7 is restricted to synonymous variants.
Sources
Identifiers
- Gene
- FGFR2
- Transcript
- NM_000141.4
- Coding (HGVS c.)
- NM_000141.4:c.2141A>C
- Protein (HGVS p.)
- NP_000132.3:p.(Lys714Thr)
- GRCh38
- chr10:121485449 T>G
- GRCh37
- chr10:123244963 T>G
Gene diagram
Every interpreted variant in FGFR2, mapped onto the exon structure of NM_000141.4. Select a row to find it on the plot.
FGFR2NM_000141.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in FGFR2
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.771
- BayesDel
- 0.170
How the predictions were used
PP3 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). Details ▾Hide ▴
Evidence considered
- REVEL: 0.771 (deleterious).
- BayesDel: 0.169711 (benign).
- SpliceAI max delta: 0.01 (no predicted splice impact).
Sources
BP4 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. Details ▾Hide ▴
Evidence considered
- REVEL: 0.771 (deleterious
- conflicts with BP4).
- BayesDel: 0.169711 (benign).
- SpliceAI max delta: 0.01 (neutral).
- No consensus for benign prediction.
Sources
BP7 N/ANM_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. Details ▾Hide ▴
Evidence considered
- Variant type: missense substitution
- BP7 is restricted to synonymous variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.771. BayesDel score = 0.169711.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_000141.4%3Ac.2141A%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-123244963-T-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-121485449-T-G?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-121485449-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000141.4%3Ac.2141…
- OncoKB ↗www.oncokb.org/gene/FGFR2/K714T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FGFR2+c.2141A%3EC
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from 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.
Functional
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.