About FGFR2
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
FGFR2 c.1223A>C, p.(Asp408Ala)
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: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant not observed in the general population.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.377 (below 0.5 threshold), BayesDel score is -0.0395 (in the benign range), and SpliceAI predicts no splicing impact (max delta score 0.00).
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 moderate, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, 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
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
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: 2 met · 19 not met · 1 not assessed · 7 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
PM2 (moderate): The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases, supporting a rare variant not observed in the general population.
BP4 (supporting benign): Multiple computational predictors (REVEL 0.377, BayesDel -0.0395, SpliceAI 0.00) suggest no significant impact on the gene product or splicing.
PVS1, PS1, PS2, PS3, PS4, PS5, PM1, PM5, PM6, PP1, PP3, PP4, PP5, BA1, BS1, BS2, BS3, BS4, BP2, BP5, BP6 are not met. BP1, BP7, BP3, PM3, PM4 are not applicable. PP2 is not assessed due to absent gnomAD constraint metrics.
Classification: Uncertain Significance (VUS). One moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4) do not meet thresholds for Likely Pathogenic (requires ≥2 moderate or ≥1 strong) or Likely Benign (requires ≥2 supporting benign).
No criteria match.
Met · 2
PM2 ModerateThis variant is absent from gnomAD v2.1, gnomAD v4.1, and gnomAD-Canada v1.0 population databases, consistent with a rare variant not observed in the general population. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes).
- Absent from gnomAD v4.1 (exomes/genomes).
- Absent from gnomAD-Canada v1.0 (genomes).
Sources
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.377 (below 0.5 threshold), BayesDel score is -0.0395 (in the benign range), and SpliceAI predicts no splicing impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL score 0.377 suggests no damaging effect.
- BayesDel score -0.0395 is in the benign prediction range.
- SpliceAI max delta 0.00 predicts no splice alteration.
Sources
Not met · 19 · evaluated, threshold not reached
PS1 No ClinVar entry exists for any variant causing the same amino acid change (p.Asp408Ala) at this position. There is no evidence that this amino acid change has been previously established as pathogenic regardless of the underlying nucleotide change. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no prior pathogenic assertion for p.Asp408Ala or any other amino acid change at this residue.
Sources
PS2 No de novo data available. No family trios or confirmed paternity/maternity de novo reports exist for this variant in the evidence packet. Details ▾Hide ▴
Evidence considered
- No de novo observation data available.
Still missing
- No family studies or de novo testing data available.
PS3 No functional studies identified for this variant or for a systematically characterized range that includes p.Asp408. Literature search returned 0 PMIDs; OncoKB reports Unknown Oncogenic Effect with no variant-specific functional evidence. Details ▾Hide ▴
Evidence considered
- No functional data identified for this variant or a systematically characterized range encompassing p.Asp408.
Still missing
- No functional studies available for adjudication.
Sources
PS4 No case-control data available. Variant is absent from ClinVar and no prevalence comparison between affected individuals and controls can be performed. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no case-control or prevalence data available.
Still missing
- No case-control studies available.
Sources
PM1 Residue 408 (Asp408) lies in the intracellular juxtamembrane region of FGFR2 between the transmembrane domain (~378-398) and the kinase domain (~481-754), which is not a recognized mutational hotspot for FGFR2-related disorders. Cancerhotspots.org reports no statistical significance at this residue, and no ClinVar entries exist for position 408. Details ▾Hide ▴
Evidence considered
- Residue 408 is not in a recognized FGFR2 mutational hotspot (cancerhotspots.org negative)
- no ClinVar entries at this position.
Sources
PM5 No same-residue comparator variants identified at position 408 in ClinVar. PM5 candidate search returned 0 candidates; no pathogenic missense variant at Asp408 has been reported against which to apply PM5. Details ▾Hide ▴
Evidence considered
- No same-residue pathogenic missense variants identified in ClinVar at FGFR2 position 408.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo reports (assumed de novo without confirmation of paternity/maternity) available for this variant in the evidence packet. Details ▾Hide ▴
Evidence considered
- No de novo observation data available.
Still missing
- No de novo testing data available.
PP1 No cosegregation data available. No family studies have been performed or reported for this variant. Details ▾Hide ▴
Evidence considered
- No cosegregation data available.
Still missing
- No family segregation data available.
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.377 (below the 0.5 threshold for damaging prediction), BayesDel score is -0.0395 (in the benign range), and SpliceAI predicts no splicing impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL score 0.377 (below 0.5 damaging threshold).
- BayesDel score -0.0395 (benign range).
- SpliceAI max delta 0.00 (no predicted splice impact).
Sources
PP4 No patient phenotype or family history data are available for disease specificity assessment. The variant was submitted without clinical context. Details ▾Hide ▴
Evidence considered
- No phenotypic data available.
Still missing
- Patient phenotype and clinical history not provided.
PP5 No reputable source has recently reported this variant as pathogenic. The variant is absent from ClinVar and no publications mention it. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no recent reports of pathogenicity from reputable sources.
Sources
BA1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- AF does not exceed 1%.
Sources
BS1 Variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. Allele frequency does not exceed the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- Absent from all population databases
- AF does not exceed 0.3%.
Sources
BS2 No evidence of this variant observed in healthy adult individuals for FGFR2-related disorders with expected full penetrance at an early age. Details ▾Hide ▴
Evidence considered
- No observations in healthy adults available.
Still missing
- No healthy adult carrier data available.
BS3 No well-established in vitro or in vivo functional studies showing no damaging effect for this variant. No functional data of any kind were identified. Details ▾Hide ▴
Evidence considered
- No functional studies identified for this variant.
Still missing
- No functional studies available.
Sources
BS4 No segregation data available to demonstrate lack of segregation with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No segregation data available.
Still missing
- No family segregation data available.
BP2 No data on observations of this variant in trans with a pathogenic variant for this dominantly inherited disorder, or in cis with a pathogenic variant in any inheritance pattern. Details ▾Hide ▴
Evidence considered
- No phase data available.
Still missing
- No phase information with known pathogenic variants.
BP5 No case has been reported where this variant was found in an individual with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No alternate molecular basis data available.
Still missing
- No cases with alternate molecular diagnosis identified.
BP6 No reputable source has recently reported this variant as benign. The variant is absent from ClinVar and no publications mention it. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no recent reports of benign classification from reputable sources.
Sources
Not assessed · 1 · no assessment recorded
PP2 gnomAD missense constraint metrics (Z-score, o/e ratio) for FGFR2 are not available in the evidence packet. While FGFR2-associated disorders are primarily caused by gain-of-function missense variants, PP2 requires quantitative evidence of low benign missense variation in the gene, which was not provided. Details ▾Hide ▴
Evidence considered
- FGFR2 disease mechanism is primarily missense
- but quantitative constraint metrics were not available in the evidence packet.
Still missing
- gnomAD missense constraint metrics (Z-score
- o/e) needed for PP2 adjudication.
Not applicable · 7· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense substitution (c.1223A>C, p.Asp408Ala); does not fall into PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. pvs1_variant_assessment confirms apply_generic_pvs1_framework=false. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a predicted null variant eligible for PVS1.
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM3 N/AFGFR2-related disorders follow autosomal dominant inheritance. PM3 (detected in trans for recessive disorders) is not applicable. Details ▾Hide ▴
No further detail was recorded.
PM4 N/AProtein length changes due to in-frame indels or stop-loss — not applicable to this missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP1 N/AFGFR2-associated disorders (craniosynostosis syndromes, skeletal dysplasias) are primarily caused by gain-of-function missense variants, not truncating variants. BP1 applies only to genes where truncating variants are the primary disease mechanism. Details ▾Hide ▴
Evidence considered
- FGFR2 disease mechanism is primarily gain-of-function missense
- BP1 does not apply.
Sources
pvs1_gene_context
BP3 N/AIn-frame indels in repeat regions without known function — not applicable to this missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.1223A>C, p.Asp408Ala), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a synonymous variant.
PS5 N/APS5 is not a criterion in the ACMG/AMP 2015 classification framework used for this adjudication. Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- FGFR2
- Transcript
- NM_000141.4
- Coding (HGVS c.)
- NM_000141.4:c.1223A>C
- Protein (HGVS p.)
- NP_000132.3:p.(Asp408Ala)
- GRCh38
- chr10:121515181 T>G
- GRCh37
- chr10:123274695 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
- 0.377
- BayesDel
- -0.040
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no significant impact on the gene product. REVEL score is 0.377 (below 0.5 threshold), BayesDel score is -0.0395 (in the benign range), and SpliceAI predicts no splicing impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL score 0.377 suggests no damaging effect.
- BayesDel score -0.0395 is in the benign prediction range.
- SpliceAI max delta 0.00 predicts no splice alteration.
Sources
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.377 (below the 0.5 threshold for damaging prediction), BayesDel score is -0.0395 (in the benign range), and SpliceAI predicts no splicing impact (max delta score 0.00). Details ▾Hide ▴
Evidence considered
- REVEL score 0.377 (below 0.5 damaging threshold).
- BayesDel score -0.0395 (benign range).
- SpliceAI max delta 0.00 (no predicted splice impact).
Sources
BP7 N/AThis is a missense variant (c.1223A>C, p.Asp408Ala), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution
- not a synonymous variant.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.377. BayesDel score = -0.0395299.
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 0.000
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.1223A%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/10-123274695-T-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr10-121515181-T-G?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/10-121515181-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000141.4%3Ac.1223…
- OncoKB ↗www.oncokb.org/gene/FGFR2/D408A
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=FGFR2+c.1223A%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 = 0.00). REVEL score = 0.377. BayesDel score = -0.0395299.
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.