NM_002253.3:c.3299C>T

KDR · NP_002244.1:p.(Ser1100Phe) · NM_002253.3

GRCh37: chr4:55955863 G>A · GRCh38: chr4:55089696 G>A

Gene: KDR Transcript: NM_002253.3

Final call

VUS

PS3 moderate PM2 supporting PP3 supporting

Variant details

Gene

KDR

Transcript

NM_002253.3

Protein

NP_002244.1:p.(Ser1100Phe)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

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.

Final determination: Generic ACMG/AMP 2015 fallback rules do not meet benign, likely benign, likely pathogenic, or pathogenic combination thresholds, so the variant is classified as Variant of Uncertain Significance.

Criteria assessment

ACMG/AMP criteria review

Criteria shown when status is available

All criteria require review: For research and educational purposes only.

Criterion	Status	Rationale	Evidence used
PVS1	N/A	NM_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).	pvs1_generic_framework
PS1	N/A	No 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.	clinvar
PS2	Not met	No de novo observation has been reported for NM_002253.3:c.3299C>T. No case-parent trio data available.
PS3	Met	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.	PMID:29588308
PS4	Not met	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.
PS5	N/A	PS5 requires an established pathogenic variant at the same residue identified via alternative mutational mechanism. No such comparator exists for this variant.
PM1	Not met	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.
PM2	Met	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.	gnomad_v2 gnomad_v4 gnomad_canada
PM5	N/A	No same-residue pathogenic comparator variants identified in ClinVar. PM5 candidate harvesting found zero candidates at position Ser1100. Classic PM5 semantics cannot be satisfied.	pm5_candidates clinvar
PM6	Not met	No de novo observation has been reported for this variant. PM6 requires a confirmed de novo occurrence with maternity and paternity confirmed.
PP1	Not met	No segregation data available for this variant. No family studies have been reported.
PP2	Not met	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.
PP3	Met	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.	revel spliceai bayesdel
PP4	Not met	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.
PP5	Not met	This variant has not been reported as pathogenic by a reputable clinical laboratory or expert panel. No ClinVar submissions exist for this variant.	clinvar
BA1	Not met	Variant is absent from gnomAD, with an allele frequency of 0, well below the 1% BA1 threshold.	gnomad_v2 gnomad_v4
BS1	Not met	Variant is absent from gnomAD, with an allele frequency of 0, well below the 0.3% BS1 threshold.	gnomad_v2 gnomad_v4
BS2	Not met	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).
BS3	Not met	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.	PMID:29588308
BS4	Not met	No segregation data available showing lack of co-segregation with disease. No family studies have been reported for this variant.
BP1	Not met	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.	PMID:29588308
BP2	Not met	No observation of this variant in trans with a known pathogenic variant in KDR. No phase data available.
BP4	Not met	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.	revel spliceai bayesdel
BP5	Not met	No observation of this variant in a case with an alternate molecular basis for disease. No such clinical data exists.
BP6	Not met	No reputable source classifies this variant as benign. The variant is absent from ClinVar. BP6 requires a reputable source reporting the variant as benign.	clinvar
BP7	N/A	NM_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.

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