CUX1c.2505G>AUncertain significance

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Variant interpretation report

CUX1 c.2505G>A, p.(Trp835Ter)

NM_001202543.1:c.2505G>A NP_001189472.1:p.(Trp835Ter) 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 CUX1

No gene-level summary was recorded for this case.

Key facts

Evidence used: 1 very strong (pathogenic) · 1 supporting (pathogenic)
Expert rules: Not recorded
Pipeline record: 9 Jul 2026 · version 7.0.1

Evidence considered

View criteria

Applied evidence criteria

PVS1 (very strong): Nonsense variant (p.Trp835Ter) in exon 18 of 24. The premature termination codon is located at nucleotide position 2505, well upstream of the last exon-exon junction at c.3920, predicting nonsense-mediated decay. CUX1 loss-of-function is an established disease mechanism supported by germline literature (CUX1-related neurodevelopmental disorder) and somatic cancer data (haploinsufficient tumor suppressor in myeloid malignancies). Under ClinGen SVI PVS1 guidance (PMC6185798), a nonsense variant in a gene with confirmed LoF mechanism receives PVS1 at very strong strength.
PM2 (supporting): This variant is absent from all population databases (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0), meeting PM2 criteria for a variant absent from controls at a frequency below 0.1%.

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: 2 Benign evidence criteria: 0

Pathogenic criteria applied · 2

PVS1Very strong

PVS1 · very strong

Nonsense variant (p.Trp835Ter) in exon 18 of 24. The premature termination codon is located at nucleotide position 2505, well upstream of the last exon-exon junction at c.3920, predicting nonsense-mediated decay. CUX1 loss-of-function is an established disease mechanism supported by germline literature (CUX1-related neurodevelopmental disorder) and somatic cancer data (haploinsufficient tumor suppressor in myeloid malignancies). Under ClinGen SVI PVS1 guidance (PMC6185798), a nonsense variant in a gene with confirmed LoF mechanism receives PVS1 at very strong strength.

PM2Supporting

PM2 · supporting

This variant is absent from all population databases (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0), meeting PM2 criteria for a variant absent from controls at a frequency below 0.1%.

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: PVS1 very strong, PM2 supporting; combination = 1 very strong + 1 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.

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

0.000 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

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 Loss-of-function; curated oncogenicity label: Likely Oncogenic.

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 Not recorded, with the data and sources behind each one.

26 criteria with recorded statuses: 2 met · 7 not met · 9 not assessed · 8 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

PVS1 (very strong): NM_001202543.1:c.2505G>A is a nonsense variant (p.Trp835Ter) in exon 18 of 24, predicted to undergo nonsense-mediated decay. CUX1 loss-of-function is an established disease mechanism.

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

Combined classification: PVS1 (very strong) + PM2 (supporting) = Likely Pathogenic per ACMG/AMP 2015 rules (PMID:25741868). One very strong criterion plus at least one supporting criterion reaches the Likely Pathogenic threshold.

Met · 2

PVS1 Very strongNonsense variant (p.Trp835Ter) in exon 18 of 24. The premature termination codon is located at nucleotide position 2505, well upstream of the last exon-exon junction at c.3920, predicting nonsense-mediated decay. CUX1 loss-of-function is an established disease mechanism supported by germline literature (CUX1-related neurodevelopmental disorder) and somatic cancer data (haploinsufficient tumor suppressor in myeloid malignancies). Under ClinGen SVI PVS1 guidance (PMC6185798), a nonsense variant in a gene with confirmed LoF mechanism receives PVS1 at very strong strength. Details ▾Hide ▴

Evidence considered

Nonsense variant predicted to cause NMD (stop codon >50 nt upstream of last exon-exon junction)
CUX1 loss-of-function mechanism supported by germline disease publications (PMID:40836298 reports CUX1 c.2637G>A p.Trp879* as likely pathogenic in GDD/ID pedigree)
Haploinsufficiency of CUX1 confirmed as disease mechanism in myeloid malignancies (PMID:23212519
PMID:24316979)

Still missing

Transcript NM_001202543.1 is not MANE Select
confirm this is the clinically relevant transcript for the patient's indication
Confirm biological relevance of exon 18 — if this exon is absent in critical isoforms or enriched for population LoF variants
downgrade may be warranted

Sources

pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

PM2 SupportingThis variant is absent from all population databases (gnomAD v2.1, gnomAD v4.1, gnomAD-Canada v1.0), meeting PM2 criteria for a variant absent from controls at a frequency below 0.1%. Details ▾Hide ▴

Evidence considered

gnomAD v2.1: 0 alleles / 0 AF
gnomAD v4.1: 0 alleles / 0 AF
gnomAD-Canada v1.0: 0 alleles / 0 AF

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Not met · 7 · evaluated, threshold not reached

PS3 No variant-specific functional studies were identified for NM_001202543.1:c.2505G>A. Gene-level evidence establishes CUX1 as a haploinsufficient tumor suppressor (PMID:23212519, PMID:24316979), but functional assays demonstrating the damaging effect of this specific nonsense variant have not been published. OncoKB classification of 'Likely Oncogenic' reflects somatic cancer context and does not constitute germline PS3 functional evidence. Details ▾Hide ▴

Evidence considered

Gene-level functional data confirms CUX1 loss-of-function is pathogenic
but no variant-specific assay for c.2505G>A exists

Still missing

Variant-specific functional studies (e.g.
RNA/protein expression
transcriptional activity assays) are not available

Sources

oncokb ↗

PM1 This variant does not lie in a statistically significant mutational hotspot (CancerHotspots.org negative). Although p.Trp835Ter truncates the protein upstream of the C-terminal homeodomain, removing critical DNA-binding regions, there is no defined functional domain hotspot with enrichment of pathogenic variants meeting PM1 criteria under generic ACMG/AMP. Details ▾Hide ▴

Evidence considered

CancerHotspots.org: residue not significant
No defined CUX1 hotspot domain in ClinGen or published curated resources

PP5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar. OncoKB classification of 'Likely Oncogenic' reflects somatic cancer context and does not constitute a germline PP5 source. Details ▾Hide ▴

Evidence considered

Absent from ClinVar
OncoKB 'Likely Oncogenic' is somatic context only

Sources

clinvar ↗oncokb ↗

BA1 This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). Does not meet BA1 threshold of >1% allele frequency. Details ▾Hide ▴

Evidence considered

gnomAD AF = 0.0% across all populations

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS1 This variant is absent from all population databases. Does not meet BS1 threshold of >0.3% allele frequency. Details ▾Hide ▴

Evidence considered

gnomAD AF = 0.0% across all populations

Sources

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

BS3 No well-established functional studies showing no damaging effect for this variant. Existing gene-level functional data (PMID:23212519, PMID:24316979) supports a damaging loss-of-function mechanism for CUX1, which is inconsistent with BS3. Details ▾Hide ▴

Evidence considered

Gene-level data supports damaging effect
not benign

BP6 No reputable source has reported this variant as benign. The variant is absent from ClinVar. Details ▾Hide ▴

Evidence considered

Absent from ClinVar

Sources

clinvar ↗

Not assessed · 9 · no assessment recorded

PS2 Insufficient evidence: PMID:41662332 reports a de novo CUX1 variant in a PANS case, but the specific variant (c.2505G>A) was not confirmed in the full text. No other de novo observation of this exact variant was identified in the literature reviewed. Details ▾Hide ▴

Still missing

Require confirmation that the CUX1 de novo variant in PMID:41662332 is NM_001202543.1:c.2505G>A
if confirmed
PS2_moderate would apply

PS4 No case-control or cohort data available for this variant. The variant is absent from ClinVar and has no reported observations in affected individuals outside of unpublished clinical testing. Details ▾Hide ▴

Still missing

No prevalence data in affected vs. control populations

PM6 No confirmed de novo observation of NM_001202543.1:c.2505G>A in a trio. PMID:41662332 reports a de novo CUX1 variant but the specific variant was not confirmed as c.2505G>A in the full text. Details ▾Hide ▴

Still missing

Confirm whether the CUX1 de novo variant in PMID:41662332 is NM_001202543.1:c.2505G>A

PP1 No segregation data available for this variant. No family studies were identified in the literature reviewed. Details ▾Hide ▴

Still missing

No family segregation data

PP4 No patient phenotype information available for this case assessment. Cannot evaluate whether the patient's clinical presentation is consistent with CUX1-related disorders (neurodevelopmental delay, intellectual disability, or myeloid malignancy predisposition). Details ▾Hide ▴

Still missing

Patient phenotype not provided for comparison with CUX1-related disorder spectrum

BS2 No data on observation in healthy adults. The variant is absent from gnomAD, which precludes assessment of BS2. Details ▾Hide ▴

Still missing

No reported observations in healthy adult controls

BS4 No segregation data available to evaluate lack of segregation with disease. Details ▾Hide ▴

Still missing

No family segregation data

BP2 No data on observation in trans with a known pathogenic variant. Details ▾Hide ▴

Still missing

No data on phase with other CUX1 variants

BP5 No data on observation in a case with an alternative molecular basis for disease. Details ▾Hide ▴

No further detail was recorded.

Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴

PS1 N/ANot applicable: PS1 requires a missense variant at the same amino acid residue as a known pathogenic missense change. This variant is a nonsense (p.Trp835Ter), not a missense substitution. Details ▾Hide ▴

No further detail was recorded.

PM5 N/ANot applicable: PM5 requires a missense change at the same amino acid residue as a known pathogenic missense variant. This is a nonsense variant (p.Trp835Ter), and no different pathogenic missense variants at codon 835 were identified. PM5 candidates search returned no same-residue comparators. Details ▾Hide ▴

Evidence considered

No alternative pathogenic missense variants at Trp835 identified in ClinVar

Sources

pm5_candidates

PP2 N/ANot applicable: PP2 applies to missense variants in genes with a low rate of benign missense variation. This is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

PP3 N/ANot applicable for a nonsense variant when PVS1 is already applied. The deleterious effect is inherent to the null variant type. SpliceAI predicts no splicing impact (max delta = 0.00), which is expected for a coding substitution that creates a stop codon. BayesDel score of 0.656 is consistent with a deleterious prediction but is redundant with the PVS1 null-effect determination. Details ▾Hide ▴

Evidence considered

SpliceAI max delta = 0.00 (no aberrant splicing predicted)
BayesDel = 0.656 (deleterious prediction consistent with null variant)

Sources

spliceai ↗bayesdel

BP1 N/ANot applicable: BP1 applies to missense variants in genes where only truncating variants cause disease. This is a nonsense (truncating) variant. Details ▾Hide ▴

No further detail was recorded.

BP4 N/ANot applicable for a nonsense variant. Multiple computational tools (BayesDel = 0.656) predict a deleterious effect rather than a benign effect, and the null effect of a nonsense variant is self-evident. SpliceAI shows no cryptic splicing (max delta = 0.00), but this is expected for a coding stop-gain substitution and does not constitute evidence of no impact. Details ▾Hide ▴

Evidence considered

BayesDel = 0.656 (deleterious
not benign)
SpliceAI max delta = 0.00

Sources

spliceai ↗bayesdel

BP7 N/ANot applicable: BP7 applies to synonymous (silent) variants with no splicing impact. This is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

PS5 N/ASkipped per instruction: trivially not_applicable. Details ▾Hide ▴

No further detail was recorded.

Identifiers

Gene: CUX1
Transcript: NM_001202543.1
Coding (HGVS c.): NM_001202543.1:c.2505G>A
Protein (HGVS p.): NP_001189472.1:p.(Trp835Ter)
GRCh38: chr7:102201769 G>A
GRCh37: chr7:101845049 G>A

Gene diagram

Every interpreted variant in CUX1, mapped onto the exon structure of NM_001202543.1. Select a row to find it on the plot.

CUX1NM_001202543.1

Fetching transcript structure from UCSC…

Exons

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Transcript span

—

Strand

—

Variants mapped

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Source

UCSC ncbiRefSeqCurated

All variants in CUX1 — 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 -338 bp

0.000

SpliceAI acceptor gainat -406 bp

0.000

SpliceAI donor lossat -45 bp

0.000

SpliceAI donor gainat +9 bp

0.000

Pangolin splice lossmagnitude shown

-0.010

Pangolin splice gain

0.000

Other predictors

REVEL: Not available
BayesDel: 0.656

How the predictions were used

Evidence considered

SpliceAI max delta = 0.00 (no aberrant splicing predicted)
BayesDel = 0.656 (deleterious prediction consistent with null variant)

Sources

spliceai ↗bayesdel

Evidence considered

BayesDel = 0.656 (deleterious
not benign)
SpliceAI max delta = 0.00

Sources

spliceai ↗bayesdel

BP7 N/ANot applicable: BP7 applies to synonymous (silent) variants with no splicing impact. This is a nonsense variant. Details ▾Hide ▴

No further detail was recorded.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). BayesDel score = 0.655873.

2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.

Recorded publications

CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia.

Identifies CUX1 as a haploinsufficient tumor suppressor gene on chromosome 7q22.1 frequently inactivated in acute myeloid leukemia through deletion or translocation. The paper demonstrates that CUX1 transcript and protein levels are reduced to ~50% in -7/del(7q) leukemias, and Drosophila cut hemocyte models confirm tumor-suppressive function. No specific variant-level data; the study examined 144 AML/t-MN samples by Sanger sequencing and found no CUX1 somatic mutations.
Does not name this variant
PMID 23212519 ↗
Quoted passage
Sanger sequencing of CUX1 exons in 144 AML/t-MNs samples, 39 of which have -7/del(7q), did not reveal any somatic mutations.
Methods (Sanger sequencing of CUX1 exons in 144 AML samples); Results (no CUX1 mutations identified)
Inactivating CUX1 mutations promote tumorigenesis.

Pan-cancer analysis of 7,651 tumor genomes identifying CUX1 as a significantly mutated tumor suppressor gene with enrichment of nonsense mutations. Demonstrates that CUX1 inactivation promotes tumorigenesis through loss of transcriptional regulation. Reports nonsense and frameshift mutations in CUX1 at 1-5% frequency across tumor types. No specific mention of NM_001202543.1:c.2505G>A or p.Trp835Ter.
Does not name this variant
PMID 24316979 ↗
Quoted passage
nonsense and frameshift deletion/insertion lesions accounted for 21% of mutations in CUX1, with 51% of mutations being missense
Results (pan-cancer mutational analysis); Supplementary Table 2 (CUX1 mutations across tumor types)

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 0.000 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 = 0.00). BayesDel score = 0.655873.

Functional

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

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.