About KDR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
KDR c.2300T>C, p.(Ile767Thr)
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
PM2Moderate
PM2 · moderate
This variant is absent from gnomAD v2.1 and is extremely rare in gnomAD v4.1 (allele frequency 1.86e-06, 3/1,613,212 alleles, 0.00019%), well below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada v1.0. The grpmax filtering allele frequency is 2.8e-07.
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 moderate; combination = 1 moderate, 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
3 / 1,613,212 alleles
gnomAD v4.1: 3 / 1,613,212 alleles. Recorded AF 1.85964e-06. Recorded homozygote count 0.
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.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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. KDR, a receptor tyrosine kinase, is altered by mutation or amplification in various cancers, most frequently in skin cancers.
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 · 8 not met · 15 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_002253.3:c.2300T>C (p.Ile767Thr) is a missense variant in the KDR gene, located in the transmembrane domain.
This variant is absent from gnomAD v2.1 and is extremely rare in gnomAD v4.1 (allele frequency 1.86e-06, 3/1,613,212 alleles), meeting PM2 at moderate strength.
The variant is absent from gnomAD-Canada v1.0 and not reported in COSMIC.
In silico predictions are equivocal: SpliceAI predicts no splice impact (max delta 0.00), REVEL score is 0.575 (borderline), and BayesDel is -0.004 (neutral). Neither PP3 nor BP4 is met.
The variant has been reported in ClinVar as Uncertain significance by a single clinical laboratory (Ambry Genetics). No submitter has classified it as pathogenic or benign.
OncoKB classifies KDR I767T as Unknown Oncogenic Effect with no curated functional evidence. No published functional studies or case-level data specific to this variant were identified.
No CSPEC or VCEP framework exists for KDR. Assessment follows generic ACMG/AMP 2015 guidelines.
The single met criterion is PM2 (moderate). No pathogenic criteria at supporting strength or higher are met beyond PM2. Insufficient evidence is available to reach a likely pathogenic or pathogenic classification.
Insufficient benign evidence is available to reach a likely benign or benign classification. The variant remains a variant of uncertain significance.
No criteria match.
Met · 1
PM2 ModerateThis variant is absent from gnomAD v2.1 and is extremely rare in gnomAD v4.1 (allele frequency 1.86e-06, 3/1,613,212 alleles, 0.00019%), well below the 0.1% threshold for PM2. It is also absent from gnomAD-Canada v1.0. The grpmax filtering allele frequency is 2.8e-07. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1.
- gnomAD v4.1: AF 1.86e-06 (3/1
- 613
- 212 alleles)
- grpmax FAF 2.8e-07.
- Absent from gnomAD-Canada v1.0.
Sources
Not met · 8 · evaluated, threshold not reached
PM1 The variant p.Ile767Thr is located in the transmembrane domain of KDR (VEGFR2), not in a statistically significant mutational hotspot. Hotspot analysis returned no significant enrichment at this residue. There is no curated evidence that the transmembrane region constitutes a critical functional domain for PM1 application in the absence of supporting case-level data. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: residue not significant
- OncoKB: no reviewed functional evidence
- variant lies in transmembrane domain (aa ~762-786)
- not a known critical functional domain.
Still missing
- No domain-level PM1 mapping or curated functional-domain data specific to KDR transmembrane region.
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta 0.00). REVEL score is 0.575 (borderline, below typical pathogenic thresholds). BayesDel score is -0.004 (neutral, slightly benign-leaning). The in silico evidence is equivocal and does not satisfy PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00 (no predicted splice impact).
- REVEL: 0.575 (borderline
- below strong pathogenic threshold).
- BayesDel: -0.004 (neutral).
Sources
PP5 No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance (criteria provided, single submitter — Ambry Genetics). Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance. No pathogenic assertion from any submitter.
Sources
BA1 The allele frequency in gnomAD v4.1 is 1.86e-06 (0.00019%), far below the 1% BA1 threshold for non-VCEP frameworks. Details ▾Hide ▴
BS1 The allele frequency in gnomAD v4.1 is 1.86e-06 (0.00019%), far below the 0.3% BS1 threshold for non-VCEP frameworks. This frequency is not greater than expected for the disorder. Details ▾Hide ▴
BP1 While KDR has literature-level support for loss-of-function as a disease mechanism in germline predisposition (familial Hodgkin lymphoma), there is insufficient evidence that KDR-related disease is caused primarily by truncating variants as opposed to missense variants. The gene-disease association remains at a research level and does not meet the threshold for BP1 application. Details ▾Hide ▴
Evidence considered
- KDR identified as a candidate germline predisposition gene with LOF mechanism supported
- but no evidence that disease is primarily driven by truncating variants.
Still missing
- No established gene-disease validity or constraint data demonstrating primarily truncating disease mechanism for KDR.
Sources
pvs1_gene_context
BP4 Multiple lines of computational evidence do not consistently suggest no impact. SpliceAI shows no splice effect (max delta 0.00). However, REVEL score is 0.575, which is borderline pathogenic-leaning and does not support benign interpretation. BayesDel is -0.004 (neutral). The in silico evidence is mixed and does not meet the requirement for multiple lines of evidence suggesting no impact on gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00.
- REVEL: 0.575 (borderline
- not clearly benign).
- BayesDel: -0.004 (neutral).
Sources
BP6 No reputable source has reported this variant as benign. ClinVar classification is Uncertain significance. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance. No benign assertion from any submitter.
Sources
Not assessed · 15 · no assessment recorded
PS1 No evidence of a different pathogenic nucleotide change at the same amino acid position (p.Ile767) was identified in ClinVar or the literature. Without a known pathogenic comparator variant at this codon, PS1 cannot be applied. Details ▾Hide ▴
Still missing
- No pathogenic variant at codon 767 identified in ClinVar or published literature.
PS2 No de novo occurrence data with confirmed paternity and maternity are available for this variant. Details ▾Hide ▴
Still missing
- No de novo testing data or trio sequencing results available.
PS3 No well-established in vitro or in vivo functional studies were identified for this variant. OncoKB classifies it as Unknown Oncogenic Effect with no reviewed functional evidence. No variant-specific functional data were found in the published literature. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect for KDR I767T
- no functional PMIDs.
Still missing
- No functional assay data (enzymatic
- binding
- expression
- or model organism) available for p.Ile767Thr.
Sources
PS4 No case-control studies or prevalence comparisons in affected vs. unaffected individuals are available. The variant is reported as VUS by a single clinical laboratory (Ambry Genetics) with no supporting case-level data. Details ▾Hide ▴
Evidence considered
- Single ClinVar submission as VUS
- no case-control or cohort prevalence data.
Still missing
- No case-control or affected-vs-control prevalence data available.
Sources
PM5 No pathogenic missense variant at the same amino acid residue (p.Ile767) was identified in ClinVar or published literature to serve as a PM5 comparator. Automated PM5 candidate harvesting found no eligible same-residue candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue comparator variants found
- no pathogenic variants at codon 767 in ClinVar.
Still missing
- No known pathogenic missense variant at codon 767 to serve as comparator.
Sources
pm5_candidates
PM6 No de novo occurrence data (with or without confirmed parentage) are available for this variant. Details ▾Hide ▴
Still missing
- No de novo reports or trio sequencing data available.
PP1 No cosegregation data in affected family members are available for this variant. Details ▾Hide ▴
Still missing
- No family-based segregation analysis available.
PP2 Insufficient data to determine whether KDR has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. The gene-disease association for KDR in the germline context is limited to research-level evidence (familial Hodgkin lymphoma predisposition) and lacks established gene-disease validity. Details ▾Hide ▴
Evidence considered
- Literature supports KDR as a candidate germline predisposition gene
- but established constraint metrics and benign missense rate data are not curated for this gene.
Still missing
- No gnomAD missense constraint metrics (Z-score
- o/e) or ClinGen gene-disease validity assessment available for KDR.
Sources
pvs1_gene_context
PP4 No proband phenotype or family history information is available to assess whether the clinical presentation is highly specific for KDR-related disease. Details ▾Hide ▴
Still missing
- No proband phenotype or clinical information provided.
BS2 No data on observation of this variant in healthy adult individuals are available to assess BS2. Details ▾Hide ▴
Still missing
- No data on variant presence in healthy adult populations or unaffected controls.
BS3 No well-established in vitro or in vivo functional studies showing no damaging effect on protein function or splicing are available for this variant. Details ▾Hide ▴
Still missing
- No functional studies demonstrating benign effect for p.Ile767Thr.
BS4 No family-based cosegregation data are available to assess lack of segregation in affected family members. Details ▾Hide ▴
Still missing
- No family segregation data available.
BP2 No data on observation of this variant in trans with a pathogenic variant in KDR or in cis with a pathogenic variant are available. Details ▾Hide ▴
Still missing
- No allele phasing data or co-occurrence data with pathogenic variants available.
BP5 No data are available identifying an alternate molecular basis for disease in a proband carrying this variant. Details ▾Hide ▴
Still missing
- No information on alternate molecular diagnoses in probands with this variant.
PS5 No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance (single submitter). Details ▾Hide ▴
Evidence considered
- ClinVar classification is VUS
- not pathogenic.
Still missing
- No reputable source reporting this variant as pathogenic.
Sources
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002253.3:c.2300T>C is a missense variant (p.Ile767Thr) that does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution — not a null variant eligible for PVS1.
Sources
PM3 N/APM3 applies to recessive disorders (detection in trans with a pathogenic variant). KDR-related germline conditions do not have established recessive inheritance; the available literature suggests dominant or uncertain inheritance patterns. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein length-altering variants (in-frame deletions/insertions, stop-loss). This variant is a missense substitution and does not alter protein length. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions/insertions in repetitive regions. This variant is a single nucleotide substitution, not an in-frame indel. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants. NM_002253.3:c.2300T>C is a missense variant (p.Ile767Thr), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense substitution — BP7 is reserved for synonymous variants.
Identifiers
- Gene
- KDR
- Transcript
- NM_002253.3
- Coding (HGVS c.)
- NM_002253.3:c.2300T>C
- Protein (HGVS p.)
- NP_002244.1:p.(Ile767Thr)
- GRCh38
- chr4:55098770 A>G
- GRCh37
- chr4:55964937 A>G
- ClinVar
- 3113930
Gene diagram
Every interpreted variant in KDR, mapped onto the exon structure of NM_002253.3. Select a row to find it on the plot.
KDRNM_002253.3
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 KDR
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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
3 / 1,613,212 alleles
AF 1.86e-06 · 0 homozygotes · FAF 2.8e-07
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.9e-06 · 3 / 1,613,212 alleles · 0 hom · FAF 2.8e-07
| African/African American1 / 74,864 | 1.3e-05 |
| European (non-Finnish)2 / 1,179,454 | 1.7e-06 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.85964e-06; MAF= 0.00019%, 3/1613212 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33576e-05; MAF= 0.00134%, 1/74864 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.575
- BayesDel
- -0.004
How the predictions were used
PP3 Multiple lines of computational evidence do not support a deleterious effect. SpliceAI predicts no splice impact (max delta 0.00). REVEL score is 0.575 (borderline, below typical pathogenic thresholds). BayesDel score is -0.004 (neutral, slightly benign-leaning). The in silico evidence is equivocal and does not satisfy PP3. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00 (no predicted splice impact).
- REVEL: 0.575 (borderline
- below strong pathogenic threshold).
- BayesDel: -0.004 (neutral).
Sources
BP4 Multiple lines of computational evidence do not consistently suggest no impact. SpliceAI shows no splice effect (max delta 0.00). However, REVEL score is 0.575, which is borderline pathogenic-leaning and does not support benign interpretation. BayesDel is -0.004 (neutral). The in silico evidence is mixed and does not meet the requirement for multiple lines of evidence suggesting no impact on gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.00.
- REVEL: 0.575 (borderline
- not clearly benign).
- BayesDel: -0.004 (neutral).
Sources
BP7 N/ABP7 applies to synonymous (silent) variants. NM_002253.3:c.2300T>C is a missense variant (p.Ile767Thr), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Missense substitution — BP7 is reserved for synonymous variants.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.575. BayesDel score = -0.00416777.
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
3 / 1,613,212 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
1 Uncertain significance
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/variation/3113930/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/4-55964937-A-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr4-55098770-A-G?dataset=gnomad_r4
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/4-55098770-A-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002253.3%3Ac.2300…
- OncoKB ↗www.oncokb.org/gene/KDR/I767T
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=KDR+c.2300T%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
This variant is present in gnomAD v4.1 (AF= 1.85964e-06; MAF= 0.00019%, 3/1613212 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33576e-05; MAF= 0.00134%, 1/74864 alleles, homozygotes = 0); grpmax FAF= 2.8e-07.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3113930)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.575. BayesDel score = -0.00416777.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. KDR, a receptor tyrosine kinase, is altered by mutation or amplification in various cancers, most frequently in skin cancers.
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.