0%
KDRc.3299C>TUncertain significance
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Variant interpretation report

KDR c.3299C>T, p.(Ser1100Phe)

NM_002253.3:c.3299C>T NP_002244.1:p.(Ser1100Phe) View identifiers
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.

About KDR

No gene-level summary was recorded for this case.

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: 3 Benign evidence criteria: 0
Pathogenic criteria applied · 3
PS3Moderate
PS3 · moderate

The KDR S1100F (VEGFR2 p.Ser1100Phe) variant was directly tested in a Colo-320 colorectal cancer cell line xenograft model. Stable expression of S1100F VEGFR2 promoted tumor growth in mice, demonstrating oncogenic functional effect (Toledo et al., 2018, PMID:29588308). Single publication with direct variant-specific functional data in a xenograft assay.

PM2Supporting
PM2 · supporting

NM_002253.3:c.3299C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare variant below the 0.1% population frequency threshold.

PP3Supporting
PP3 · supporting

REVEL score of 0.904 strongly predicts a deleterious effect for this missense variant. SpliceAI max delta score is 0.02, indicating no significant splice impact, consistent with the predicted effect being at the amino acid level. BayesDel score of 0.434 is equivocal.

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: PS3 moderate, PM2 supporting, PP3 supporting; combination = 1 moderate + 2 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.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
13 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV55764136, n = 13 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 3 met · 18 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_002253.3:c.3299C>T (p.Ser1100Phe) is a missense variant in exon 24 of KDR encoding the VEGFR2 receptor tyrosine kinase.

This variant is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0 (PM2).

In silico prediction with REVEL score of 0.904 supports a deleterious effect on protein function (PP3).

Functional studies demonstrate that S1100F VEGFR2 promotes tumor growth in a colorectal cancer cell line xenograft model, confirming oncogenic potential (PS3_moderate; Toledo et al., 2018).

The variant has been observed in somatic cancers (COSMIC COSV55764136, n=13) and is classified as Likely Oncogenic by OncoKB.

No de novo observations, segregation data, clinical case reports, or same-residue pathogenic comparators are available.

Applying generic ACMG/AMP 2015 combination rules (PMID:25741868): one moderate criterion (PS3) plus two supporting criteria (PM2, PP3) = Likely Pathogenic.

Met · 3

PS3 ModerateThe KDR S1100F (VEGFR2 p.Ser1100Phe) variant was directly tested in a Colo-320 colorectal cancer cell line xenograft model. Stable expression of S1100F VEGFR2 promoted tumor growth in mice, demonstrating oncogenic functional effect (Toledo et al., 2018, PMID:29588308). Single publication with direct variant-specific functional data in a xenograft assay. Details ▾Hide ▴
Evidence considered
  • S1100F VEGFR2 directly tested in Colo-320 xenograft model
  • promoted tumor growth in mice reaching humane endpoint.
  • S1100F was one of nine VEGFR2 cancer-associated mutants tested
  • empty vector and kinase-dead K868M controls did not generate tumors.
Still missing
  • Functional data is from a single study in a somatic cancer context (colorectal cancer cell line xenograft)
  • not germline.
  • No kinase assay
  • phosphorylation data
  • or drug sensitivity testing specific to S1100F
  • deep characterization focused on L840F and R1032Q.
  • No independent replication of the S1100F functional finding.
Sources
PMID:29588308 ↗
PM2 SupportingNM_002253.3:c.3299C>T is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare variant below the 0.1% population frequency threshold. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (0 alleles).
  • Absent from gnomAD v4.1 (0 alleles).
  • Absent from gnomAD-Canada v1.0 (0 alleles).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
PP3 SupportingREVEL score of 0.904 strongly predicts a deleterious effect for this missense variant. SpliceAI max delta score is 0.02, indicating no significant splice impact, consistent with the predicted effect being at the amino acid level. BayesDel score of 0.434 is equivocal. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.904 (highly deleterious prediction).
  • SpliceAI max delta 0.02 (no splicing impact).
  • BayesDel score 0.434 (equivocal).
Still missing
  • HCI prior not available for KDR
  • no gene-specific in silico calibration.
Sources
revelspliceai ↗bayesdel

Not met · 18 · evaluated, threshold not reached

PS2 No de novo observation has been reported for NM_002253.3:c.3299C>T. No case-parent trio data available. Details ▾Hide ▴
Evidence considered
  • No de novo data identified in any source.
Still missing
  • No trio or de novo data available for this variant.
PS4 No case-control or patient cohort data available. The variant is absent from ClinVar and population databases. No enriched prevalence in affected individuals has been demonstrated. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no clinical case observations.
Still missing
  • No case-control or patient cohort studies including this variant.
PM1 The variant does not lie in a statistically significant mutational hotspot (cancerhotspots.org negative). Ser1100 is in the C-terminal region of the VEGFR2 kinase domain but is not within a well-characterized functional motif or domain-level hotspot. No residue-specific functional domain disruption has been demonstrated for S1100F. Details ▾Hide ▴
Evidence considered
  • Not in a cancerhotspots.org statistically significant hotspot.
  • Ser1100 is within the VEGFR2 kinase domain (aa 834-1160) but not at a characterized functional motif.
PM6 No de novo observation has been reported for this variant. PM6 requires a confirmed de novo occurrence with maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
  • No de novo data identified.
Still missing
  • No de novo case reports available.
PP1 No segregation data available for this variant. No family studies have been reported. Details ▾Hide ▴
Evidence considered
  • No segregation or family data available.
Still missing
  • No family studies including this variant.
PP2 KDR does not have an established low rate of benign missense variation in a germline disease context. No HCI prior probability is available for this gene. Missense variants are not established as a common mechanism of germline disease for KDR. Details ▾Hide ▴
Evidence considered
  • HCI prior not available for KDR
  • germline missense disease mechanism not well-established.
Still missing
  • No HCI prior for KDR
  • uncertain germline missense constraint.
PP4 No clinical phenotype data available for patients carrying this variant. The variant has not been observed in a clinical diagnostic setting with a phenotype consistent with KDR-related disease. Details ▾Hide ▴
Evidence considered
  • Variant not observed in clinical cases
  • absent from ClinVar.
Still missing
  • No clinical phenotype data for variant carriers.
PP5 This variant has not been reported as pathogenic by a reputable clinical laboratory or expert panel. No ClinVar submissions exist for this variant. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no reputable source classifies this as pathogenic.
Sources
clinvar ↗
BA1 Variant is absent from gnomAD, with an allele frequency of 0, well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
  • Allele frequency is 0 in all gnomAD populations.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS1 Variant is absent from gnomAD, with an allele frequency of 0, well below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
  • Allele frequency is 0 in all gnomAD populations.
Sources
gnomad_v2 ↗gnomad_v4 ↗
BS2 No observation in healthy adult controls. Absent from gnomAD, precluding assessment of BS2 (observed in a healthy adult with full penetrance expected at an early age). Details ▾Hide ▴
Evidence considered
  • Variant absent from population databases
  • no control observations.
Still missing
  • No control cohort data available.
BS3 Functional data from PMID:29588308 demonstrates that S1100F VEGFR2 promotes tumor growth in a xenograft model, consistent with a deleterious (oncogenic) effect, not a benign effect. BS3 requires well-established in vitro or in vivo functional studies showing no damaging effect. Details ▾Hide ▴
Evidence considered
  • S1100F VEGFR2 promoted tumor growth in Colo-320 xenograft model.
  • Functional effect is deleterious/oncogenic
  • not benign.
Sources
PMID:29588308 ↗
BS4 No segregation data available showing lack of co-segregation with disease. No family studies have been reported for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation or family data available.
Still missing
  • No segregation data to assess BS4.
BP1 BP1 applies to missense variants in genes where only truncating variants are known to cause disease. KDR has reported missense variants with functional consequences (PMID:29588308), so the BP1 assumption does not hold. Details ▾Hide ▴
Evidence considered
  • Missense variants in KDR (e.g.
  • S1100F
  • L840F
  • R1032Q) have demonstrated functional consequences.
Sources
PMID:29588308 ↗
BP2 No observation of this variant in trans with a known pathogenic variant in KDR. No phase data available. Details ▾Hide ▴
Evidence considered
  • No in trans observations available.
Still missing
  • No phasing data available.
BP4 REVEL score of 0.904 strongly predicts a deleterious effect, inconsistent with BP4 which requires multiple lines of computational evidence suggesting no impact. SpliceAI shows no splicing impact (max delta 0.02), but the missense prediction is unequivocally deleterious. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.904 (deleterious).
  • SpliceAI max delta 0.02 (no splice impact).
  • In silico evidence does not support benign effect.
Sources
revelspliceai ↗bayesdel
BP5 No observation of this variant in a case with an alternate molecular basis for disease. No such clinical data exists. Details ▾Hide ▴
Evidence considered
  • No clinical cases with alternate molecular diagnosis reported.
Still missing
  • No clinical cases available for BP5 assessment.
BP6 No reputable source classifies this variant as benign. The variant is absent from ClinVar. BP6 requires a reputable source reporting the variant as benign. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign classification from any reputable source.
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002253.3:c.3299C>T is a missense variant (p.Ser1100Phe); it does not fall into the default 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 variant
  • not a null variant eligible for PVS1.
Sources
pvs1_generic_framework ↗
PS1 N/ANo known pathogenic variant at the same amino acid position (Ser1100) with a different amino acid change has been identified in ClinVar. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no same-residue pathogenic comparator available.
Sources
clinvar ↗
PM5 N/ANo same-residue pathogenic comparator variants identified in ClinVar. PM5 candidate harvesting found zero candidates at position Ser1100. Classic PM5 semantics cannot be satisfied. Details ▾Hide ▴
Evidence considered
  • No pathogenic missense variants at the same residue (Ser1100) in ClinVar.
Sources
pm5_candidatesclinvar ↗
BP7 N/ANM_002253.3:c.3299C>T is a missense variant (p.Ser1100Phe), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is restricted to synonymous variants.
PS5 N/APS5 requires an established pathogenic variant at the same residue identified via alternative mutational mechanism. No such comparator exists for this variant. Details ▾Hide ▴
Evidence considered
  • No established pathogenic variant at Ser1100 with alternative nucleotide change.

Identifiers

Gene
KDR
Transcript
NM_002253.3
Coding (HGVS c.)
NM_002253.3:c.3299C>T
Protein (HGVS p.)
NP_002244.1:p.(Ser1100Phe)
GRCh38
chr4:55089696 G>A
GRCh37
chr4:55955863 G>A
COSMIC
COSV55764136

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…
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

SpliceAI acceptor lossat -110 bp
0.020
SpliceAI acceptor gainat +17 bp
0.000
SpliceAI donor lossat -1 bp
0.000
SpliceAI donor gainat +187 bp
0.000
Pangolin splice lossmagnitude shown
-0.050
Pangolin splice gain
0.000

Other predictors

REVEL
0.904
BayesDel
0.434

How the predictions were used

PP3 SupportingREVEL score of 0.904 strongly predicts a deleterious effect for this missense variant. SpliceAI max delta score is 0.02, indicating no significant splice impact, consistent with the predicted effect being at the amino acid level. BayesDel score of 0.434 is equivocal. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.904 (highly deleterious prediction).
  • SpliceAI max delta 0.02 (no splicing impact).
  • BayesDel score 0.434 (equivocal).
Still missing
  • HCI prior not available for KDR
  • no gene-specific in silico calibration.
Sources
revelspliceai ↗bayesdel
BP4 REVEL score of 0.904 strongly predicts a deleterious effect, inconsistent with BP4 which requires multiple lines of computational evidence suggesting no impact. SpliceAI shows no splicing impact (max delta 0.02), but the missense prediction is unequivocally deleterious. Details ▾Hide ▴
Evidence considered
  • REVEL score 0.904 (deleterious).
  • SpliceAI max delta 0.02 (no splice impact).
  • In silico evidence does not support benign effect.
Sources
revelspliceai ↗bayesdel
BP7 N/ANM_002253.3:c.3299C>T is a missense variant (p.Ser1100Phe), not a synonymous variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 is restricted to synonymous variants.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.904. BayesDel score = 0.433866.

2 paper records listed. 1 cited in the classification.

Cited in the classification

  • Exome Sequencing of Plasma DNA Portrays the Mutation Landscape of Colorectal Cancer and Discovers Mutated VEGFR2 Receptors as Modulators of Antiangiogenic Therapies.
    S1100F VEGFR2 was tested alongside eight other cancer-associated VEGFR2 mutants in a Colo-320 colorectal cancer cell line xenograft model. Stable expression of S1100F VEGFR2 promoted tumor growth in mice, with tumors reaching the established humane endpoint, whereas empty vector and kinase-dead K868M controls did not generate tumors within 120 days. No kinase assay, phosphorylation, or drug sensitivity data specific to S1100F are reported.
    → PS3 Names this variant
    PMID 29588308 ↗
    Source detail
    Colo-320 cells stably expressing D717V, G800D, G800R, L840F, G843D, S925F, R1022Q, R1032Q, and S1100F VEGFR2, when injected in mice, even in small numbers and without Matrigel, could generate tumors that reached the established humane endpoint.

    Location Abstract (line 80); Results, Xenograft section (lines 539-548); Figure 2D protein diagram (line 775)

    Context Colo-320 colorectal cancer cell line xenograft model, nude mice, subcutaneous injection of 4x10^5 cells, tumor growth monitored up to 120 days

Other recorded publications

  • Genomic analysis of metastatic cutaneous squamous cell carcinoma.
    Genomic analysis of metastatic cutaneous squamous cell carcinoma using targeted sequencing of 504 cancer-associated genes on lymph node metastases from 29 patients. KDR/VEGFR2 and the variant NM_002253.3:c.3299C>T (p.Ser1100Phe) were not identified in this paper.
    Does not name this variant
    PMID 25589618 ↗

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 0.020 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

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 = 0.02). REVEL score = 0.904. BayesDel score = 0.433866.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Gain-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV55764136, n = 13 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.