Classification rationale

PVS1PM2 VUS

FLT3 c.2246C>A

NM_004119.2:c.2246C>A (p.Ser749Ter) is a nonsense variant in exon 18 of 24 in FLT3. The variant is predicted to undergo nonsense-mediated decay, and germline FLT3 loss of function is associated with autoimmune thyroid disease risk (PVS1_VeryStrong met).¹ The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.² No additional pathogenic or benign criteria are met. PVS1_VeryStrong plus PM2_Supporting does not reach the threshold for Likely Pathogenic (requires PVS1_VeryStrong plus at least two Supporting or one Moderate criterion). The variant is classified as a Variant of Uncertain Significance.³ The local FLT3 ITD framework criteria (PM1, PM5, PS3, PM4, BP3) are designed for in-frame internal tandem duplications and activating length mutations and do not apply to this nonsense substitution variant.⁴

PVS1 + PM2 → VUS

1 pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 final_classification_framework

4 vcep_flt3_itd_hotspot_and_functionvcep_flt3_oncokb_guidance

Gene diagram · NM_004119.2 · variants mapped to exon structure

FLT3 NM_004119.2

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 21 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

NM_004119.2:c.2246C>A is a nonsense variant (p.Ser749Ter) in exon 18 of 24. The predicted transcript is expected to undergo nonsense-mediated decay. Germline FLT3 loss-of-function is associated with autoimmune thyroid disease risk (PMID:32581359), satisfying the PVS1 gene-level gate. Under PMC6185798, nonsense variants upstream of the last exon in genes with an established LoF disease mechanism qualify for PVS1 at very strong strength.

Nonsense variant p.Ser749Ter in exon 18 of 24 exonsNMD expected — truncation not in the last exon or within 50 nt of the last exon-exon junctionFLT3 germline LoF associated with autoimmune thyroid disease (PMID:32581359)

pvs1_generic_framework ↗

✓

PM2 supporting Pathogenic

NM_004119.2:c.2246C>A is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, supporting a pathogenic role under PM2 at supporting strength.

Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (genomes)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS2 No de novo data are available for this variant.

PS3 No variant-specific functional data exist for NM_004119.2:c.2246C>A (p.Ser749Ter).

PS4 No case-control or cohort data are available for this variant.

PM1 The local FLT3 framework PM1 is specific to in-frame ITDs and activating length mutations in the juxtamembrane hotspot (codons 589-599) and does not cover nonsense variants.

PM5 The local FLT3 framework PM5 is specific to novel in-frame ITDs and activating length mutations in the juxtamembrane hotspot class and does not apply to this nonsense variant.

PM6 No de novo data are available for this variant, and no confirmed maternity/paternity testing has been reported.

PP1 No segregation data are available for this variant.

PP2 HCI Prior score is not available for FLT3, and no gene-specific constraint data support PP2.

PP3 SpliceAI predicts no significant splice impact (max delta score 0.07, below the 0.1 threshold).

PP4 No phenotype or clinical data are available for individuals carrying this variant.

PP5 This variant is absent from ClinVar and has not been classified by any expert panel or reputable source.

Benign

BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS1 This variant is absent from gnomAD and does not exceed the 0.3% threshold for BS1.

BS2 No homozygous observations are reported for this variant in gnomAD.

BS3 No functional studies demonstrating no deleterious effect are available for this variant.

BS4 No segregation data are available to demonstrate lack of cosegregation with disease.

BP1 BP1 applies to missense variants where a truncating mechanism is known to cause disease.

BP2 No observation of this variant in trans with a known pathogenic FLT3 variant has been reported.

BP4 While SpliceAI (max delta 0.07) and BayesDel (0.257) predict no significant impact on splicing or protein function, BP4 is not applicable to nonsense variants whose primary disease mechanism is through protein truncation and NMD rather than through splicing effects or missense-level computational features.

BP5 No observation of this variant in cis with a known pathogenic variant has been reported.

BP6 This variant is absent from ClinVar and has not been classified as benign by any reputable source.

N/A · 2 PS1 · BP7

Research & evidence

Population frequency

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). BayesDel score = 0.257456.

SpliceAI ↗

Functional Unknown Oncogenic Effect

OncoKB identified curated literature and non-variant-specific oncogenicity context for review; listed oncogenicity label: Unknown Oncogenic Effect.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots