Variant classification summary

NM_001202543.1:c.2505G>A

CUX1 · NP_001189472.1:p.(Trp835Ter) · NM_001202543.1

GRCh37: chr7:101845049 G>A · GRCh38: chr7:102201769 G>A

Gene: CUX1 Transcript: NM_001202543.1

Final call

VUS

PVS1 very strong PM2 supporting

Variant details

Gene

CUX1

Transcript

NM_001202543.1

Protein

NP_001189472.1:p.(Trp835Ter)

gnomAD AF

ClinVar

OncoKB

Likely Oncogenic

Classification rationale

Interpretation summary

Generated evidence synthesis

1

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.

2

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

3

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.

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	Met	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.	pvs1_generic_framework pvs1_gene_context pvs1_variant_assessment
PS1	N/A	Not 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.
PS2	Not assessed	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.
PS3	Not met	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.	oncokb
PS4	Not assessed	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.
PS5	N/A	Skipped per instruction: trivially not_applicable.
PM1	Not met	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.
PM2	Met	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 gnomad_v4 gnomad_canada
PM5	N/A	Not 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.	pm5_candidates
PM6	Not assessed	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.
PP1	Not assessed	No segregation data available for this variant. No family studies were identified in the literature reviewed.
PP2	N/A	Not applicable: PP2 applies to missense variants in genes with a low rate of benign missense variation. This is a nonsense variant.
PP3	N/A	Not 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.	spliceai bayesdel
PP4	Not assessed	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).
PP5	Not met	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.	clinvar oncokb
BA1	Not met	This variant is absent from all population databases (gnomAD v2.1, v4.1, Canada). Does not meet BA1 threshold of >1% allele frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS1	Not met	This variant is absent from all population databases. Does not meet BS1 threshold of >0.3% allele frequency.	gnomad_v2 gnomad_v4 gnomad_canada
BS2	Not assessed	No data on observation in healthy adults. The variant is absent from gnomAD, which precludes assessment of BS2.
BS3	Not met	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.
BS4	Not assessed	No segregation data available to evaluate lack of segregation with disease.
BP1	N/A	Not applicable: BP1 applies to missense variants in genes where only truncating variants cause disease. This is a nonsense (truncating) variant.
BP2	Not assessed	No data on observation in trans with a known pathogenic variant.
BP4	N/A	Not 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.	spliceai bayesdel
BP5	Not assessed	No data on observation in a case with an alternative molecular basis for disease.
BP6	Not met	No reputable source has reported this variant as benign. The variant is absent from ClinVar.	clinvar
BP7	N/A	Not applicable: BP7 applies to synonymous (silent) variants with no splicing impact. This is a nonsense variant.

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