Classification rationale

PVS1PM2 VUS

CUX1 c.2505G>A

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.¹ PM2 (supporting): This variant is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada).² 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.³

PVS1 + PM2 → VUS

1 pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment

2 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

3 generic_acmg_combination_rules

Gene diagram · NM_001202543.1 · variants mapped to exon structure

CUX1 NM_001202543.1

Fetching transcript structure from UCSC…

Applied criteria · 2 applied · 16 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong review Pathogenic

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.

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

pvs1_generic_framework ↗

✓

PM2 supporting Pathogenic

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%.

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

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

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.

PS3 No variant-specific functional studies were identified for NM_001202543.1:c.2505G>A.

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

PM1 This variant does not lie in a statistically significant mutational hotspot (CancerHotspots.org negative).

PM6 No confirmed de novo observation of NM_001202543.1:c.2505G>A in a trio.

PP1 No segregation data available for this variant.

PP4 No patient phenotype information available for this case assessment.

PP5 No reputable source has reported this variant as pathogenic.

Benign

BA1 This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada).

BS1 This variant is absent from all population databases.

BS2 No data on observation in healthy adults.

BS3 No well-established functional studies showing no damaging effect for this variant.

BS4 No segregation data available to evaluate lack of segregation with disease.

BP2 No data on observation in trans with a known pathogenic variant.

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

BP6 No reputable source has reported this variant as benign.

N/A · 7 PS1 · PM5 · PP2 · PP3 · BP1 · BP4 · 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 = 0.00). BayesDel score = 0.655873.

SpliceAI ↗

Functional Likely Oncogenic

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

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

Triaged references · 2 PMIDs not cited in assessment

23212519 ↗ CUX1 is a haploinsufficient tumor suppressor gene on chromosome 7 frequently inactivated in acute myeloid leukemia. ONCOKB

24316979 ↗ Inactivating CUX1 mutations promote tumorigenesis. ONCOKB