FLT3c.2246C>AUncertain significance

Print report

Variant interpretation report

FLT3 c.2246C>A, p.(Ser749Ter)

NM_004119.2:c.2246C>A NP_004110.2:p.(Ser749Ter) 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 FLT3

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: Local FLT3 ITD / activating length-mutation framework
Pipeline record: 18 Jul 2026 · version 7.0.4

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): 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.
PM2 (supporting): 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.

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 Local FLT3 ITD / activating length-mutation framework. 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: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Very strong

PVS1 · very strong

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.

PM2Supporting

PM2 · supporting

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.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Uncertain significance

PVS1_VeryStrong + PM2_Supporting. The local FLT3 ITD framework requires PVS1_VeryStrong + 2 Supporting or PVS1_VeryStrong + 1 Moderate for Likely Pathogenic. With only 1 supporting criterion met, the combination falls short of LP and no benign criteria are met, resulting in 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.

Applied · PM2 →

gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗

SpliceAI score

0.070 maximum delta

Recorded SpliceAI maximum delta score: 0.070. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗

ClinVar submissions

Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗

Functional evidence

Statement recorded

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

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

COSMIC ↗Cancer Hotspots ↗

For specialists

Technical detail

ACMG/AMP criteria under Local FLT3 ITD / activating length-mutation framework, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic

PVS1 PS1 PS2 PS3 PS4 PM1 PM2 PM5 PM6 PP1 PP2 PP3 PP4 PP5 PS5

Benign

BA1 BS1 BS2 BS3 BS4 BP1 BP2 BP4 BP5 BP6 BP7

Met Not met Not assessed Not applicable

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).

The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.

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.

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.

Met · 2

PVS1 Very strongNM_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. Details ▾Hide ▴

Evidence considered

Nonsense variant p.Ser749Ter in exon 18 of 24 exons
NMD expected — truncation not in the last exon or within 50 nt of the last exon-exon junction
FLT3 germline LoF associated with autoimmune thyroid disease (PMID:32581359)
Truncation removes approximately 245 C-terminal amino acids (~25% of protein)
including part of the tyrosine kinase domain

Still missing

FLT3 germline LoF disease mechanism is supported by a single study (PMID:32581359) for autoimmune thyroid disease
the primary FLT3 disease mechanism in the literature is somatic gain-of-function

Sources

pvs1_generic_framework ↗pvs1_variant_assessmentpvs1_gene_context

PM2 SupportingNM_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. Details ▾Hide ▴

Evidence considered

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

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 21 · evaluated, threshold not reached

PS2 No de novo data are available for this variant. Details ▾Hide ▴

Still missing

No de novo testing has been reported for this variant

PS3 No variant-specific functional data exist for NM_004119.2:c.2246C>A (p.Ser749Ter). The OncoKB entry for S749* lists 'Unknown Oncogenic Effect' and provides no functional annotation. The local FLT3 framework PS3 rule is specific to in-frame ITDs and activating length mutations with OncoKB gain-of-function support, and does not apply to this nonsense variant. No experimental functional studies were identified in the literature. Details ▾Hide ▴

Evidence considered

OncoKB classification: Unknown Oncogenic Effect for S749* — no gain-of-function annotation available

Still missing

No functional studies have tested this exact nonsense variant

Sources

oncokb ↗

PS4 No case-control or cohort data are available for this variant. The variant is absent from ClinVar and COSMIC. Details ▾Hide ▴

Still missing

No case-control studies or cohort enrichment data available

Sources

clinvar ↗

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. Under generic ACMG/AMP, PM1 requires location in a mutational hotspot or critical functional domain without benign variation. While p.Ser749Ter lies within the tyrosine kinase domain (aa 604-953), cancerhotspots.org identifies no statistically significant hotspot at this residue, and applying domain-level PM1 to a truncating variant would partially overlap with the PVS1 loss-of-function rationale. Details ▾Hide ▴

Evidence considered

Variant is at codon 749 in the kinase domain
not in the canonical FLT3 juxtamembrane ITD hotspot (codons 589-599)
No statistically significant hotspot at residue S749 per cancerhotspots.org

Sources

vcep_flt3_itd_hotspot_and_function

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. Under generic ACMG/AMP, PM5 requires a different pathogenic missense variant at the same residue. No pathogenic or likely pathogenic variant at codon S749 is present in ClinVar, and this variant is a nonsense change rather than a missense. Details ▾Hide ▴

Evidence considered

PM5 candidates search returned 0 comparators at codon 749
No P/LP ClinVar entries at residue S749
Variant is a nonsense change
not eligible for classic missense PM5

Sources

pm5_candidatesclinvar ↗vcep_flt3_itd_hotspot_and_function

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

Still missing

No de novo testing reported for this variant

PP1 No segregation data are available for this variant. Details ▾Hide ▴

Still missing

No family segregation studies reported

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

Still missing

HCI Prior gene constraint data not available for FLT3

PP3 SpliceAI predicts no significant splice impact (max delta score 0.07, below the 0.1 threshold). BayesDel score is 0.257, which is below commonly used pathogenic thresholds. REVEL score is not available. Multiple lines of computational evidence do not support a deleterious effect on splicing, and this nonsense variant's pathogenicity is mediated through protein truncation rather than missense-level computational features. Details ▾Hide ▴

Evidence considered

SpliceAI max delta score: 0.07 (no predicted splice impact)
BayesDel score: 0.257 (below pathogenic threshold)

Sources

spliceai ↗bayesdel

PP4 No phenotype or clinical data are available for individuals carrying this variant. Details ▾Hide ▴

Still missing

No clinical phenotype data available

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

Sources

clinvar ↗

BA1 This variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency does not exceed the 1% threshold for BA1. Details ▾Hide ▴

Evidence considered

Absent from all population databases

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

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

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS2 No homozygous observations are reported for this variant in gnomAD. Details ▾Hide ▴

Sources

gnomad_v2 ↗gnomad_v4 ↗

BS3 No functional studies demonstrating no deleterious effect are available for this variant. Details ▾Hide ▴

Still missing

No functional studies have tested this variant

BS4 No segregation data are available to demonstrate lack of cosegregation with disease. Details ▾Hide ▴

Still missing

No family segregation studies available

BP1 BP1 applies to missense variants where a truncating mechanism is known to cause disease. This variant is itself a nonsense (truncating) variant, so BP1 does not apply. Details ▾Hide ▴

No further detail was recorded.

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

Still missing

No data on trans observations with pathogenic variants

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. Details ▾Hide ▴

Evidence considered

SpliceAI max delta: 0.07 (benign)
BayesDel: 0.257 (benign-range)

Sources

spliceai ↗bayesdel

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

Still missing

No data on cis observations with pathogenic variants

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

Sources

clinvar ↗

Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/APS1 requires the same amino acid change to have been previously classified pathogenic. This is a nonsense variant with no prior ClinVar entry for any variant at this position. Details ▾Hide ▴

Sources

clinvar ↗

BP7 N/ABP7 applies to silent variants or intronic variants outside splice sites. This is a nonsense (stop-gain) variant, not a synonymous or intronic change. Details ▾Hide ▴

No further detail was recorded.

PS5 N/APS5 applies when a different nucleotide change at the same position results in the same amino acid change and has been classified pathogenic. This is a nonsense variant with no other pathogenic nucleotide change at c.2246. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: FLT3
Transcript: NM_004119.2
Coding (HGVS c.): NM_004119.2:c.2246C>A
Protein (HGVS p.): NP_004110.2:p.(Ser749Ter)
GRCh38: chr13:28024905 G>T
GRCh37: chr13:28599042 G>T

Gene diagram

Every interpreted variant in FLT3, mapped onto the exon structure of NM_004119.2. Select a row to find it on the plot.

FLT3NM_004119.2

Fetching transcript structure from UCSC…

Exons

—

Transcript span

—

Strand

—

Variants mapped

—

Source

UCSC ncbiRefSeqCurated

All variants in FLT3 — 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

SpliceAI acceptor lossat +38 bp

0.070

SpliceAI acceptor gainat +23 bp

0.000

SpliceAI donor lossat -44 bp

0.030

SpliceAI donor gainat +379 bp

0.010

Pangolin splice lossmagnitude shown

-0.110

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: 0.257

How the predictions were used

Evidence considered

SpliceAI max delta score: 0.07 (no predicted splice impact)
BayesDel score: 0.257 (below pathogenic threshold)

Sources

spliceai ↗bayesdel

Evidence considered

SpliceAI max delta: 0.07 (benign)
BayesDel: 0.257 (benign-range)

Sources

spliceai ↗bayesdel

BP7 N/ABP7 applies to silent variants or intronic variants outside splice sites. This is a nonsense (stop-gain) variant, not a synonymous or intronic change. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

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

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 0.070 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 = 0.07). BayesDel score = 0.257456.

Functional

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

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.