Variant classification summary

NM_001202543.1:c.1227G>A

CUX1 · NP_001189472.1:p.(Ala409=) · NM_001202543.1

GRCh37: chr7:101838855 G>A · GRCh38: chr7:102195575 G>A

Gene: CUX1 Transcript: NM_001202543.1

Final call

VUS

PM2 moderate BP4 supporting benign

Variant details

Gene

CUX1

Transcript

NM_001202543.1

Protein

NP_001189472.1:p.(Ala409=)

gnomAD AF

ClinVar

OncoKB

Unknown Oncogenic Effect

Classification rationale

Interpretation summary

Generated evidence synthesis

1

The CUX1 NM_001202543.1:c.1227G>A (NP_001189472.1:p.(Ala409=)) variant has not been reported in ClinVar, and curated cancer review resources did not provide variant-specific oncogenic evidence.

2

This variant is very rare in population databases, with allele frequencies of 8.17e-06 (2/244722; 0.00082%) in gnomAD v2.1 and 8.07e-06 (13/1611678; 0.00081%) in gnomAD v4.1.

3

CUX1 loss of function is an established germline disease mechanism, but this synonymous variant is not a generic PVS1-eligible loss-of-function variant.

4

Computational splice prediction does not support a damaging effect, as SpliceAI predicts no significant splice impact with a maximum delta score of 0.00.

Final determination: Generic ACMG/AMP 2015 fallback rules identified both pathogenic and benign evidence, so the overall classification remains Variant of Uncertain Significance because the evidence is conflicting.

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	Not met	CUX1 loss of function is an established germline disease mechanism, but this variant is a synonymous change, is not in a canonical +/-1,2 splice position, and does not fall into the generic PVS1 null-variant categories; available evidence does not support applying PVS1.	pvs1_gene_context pvs1_variant_assessment pvs1_generic_framework
PS1	N/A	PS1 is not applicable because this is a synonymous variant and no evidence was identified that it produces the same amino acid change as an established pathogenic variant.	clinvar
PS2	Not assessed	No confirmed de novo occurrence with verified maternity and paternity was identified for this variant.
PS3	Not assessed	No well-established functional study was identified for this exact variant.	oncokb
PS4	Not assessed	No case enrichment, case-control, or multiple affected-individual observations were identified for this variant.	clinvar
PM1	Not met	Available data do not place this variant in a well-established critical functional domain or statistically significant hotspot; Cancer Hotspots did not identify a significant hotspot at Ala409.	hotspots oncokb
PM2	Met	This variant is very rare in population databases, with gnomAD v2.1 AF 8.17e-06 (0.00082%; 2/244722) and gnomAD v4.1 AF 8.07e-06 (0.00081%; 13/1611678), both well below the 0.1% PM2 threshold.	gnomad_v2 gnomad_v4
PM3	N/A	No recessive disease context or trans observation data were identified to support PM3 for this variant.
PM4	N/A	PM4 is not applicable because this variant is a synonymous substitution and does not change protein length.
PM5	N/A	PM5 is not applicable because this is not a missense variant, and same-residue PM5 comparator logic could not be applied.	pm5_candidates
PM6	Not assessed	No presumed de novo occurrence was identified for this variant.
PP1	Not assessed	No segregation data were identified for this variant.
PP2	N/A	PP2 is not applicable because this is not a missense variant.
PP3	Not met	Available computational evidence does not support a damaging effect: SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, and no additional damaging REVEL, BayesDel, or HCI prior evidence was identified.	spliceai
PP4	Not assessed	No phenotype information was provided that is sufficiently specific to assess PP4 for this variant.
PP5	Not met	No reputable external classification source identifying this variant as pathogenic was found; the variant is absent from ClinVar.	clinvar
BA1	Not met	Population frequency does not meet the BA1 threshold: the highest observed overall allele frequency is 8.07e-06 (0.00081%) in gnomAD v4.1, which is far below the 1% BA1 threshold.	gnomad_v4
BS1	Not met	Population frequency does not meet the BS1 threshold: the highest observed population frequency is 1.33e-05 (0.00133%) in gnomAD v4.1 African/African American samples, which is below the 0.3% BS1 threshold.	gnomad_v4
BS2	Not assessed	No evidence was identified showing this variant in healthy adult individuals at a frequency or zygosity sufficient to support BS2.	gnomad_v2 gnomad_v4
BS3	Not assessed	No well-established functional study was identified showing no damaging effect for this exact variant.	spliceai
BS4	Not assessed	No family data were identified showing lack of segregation with disease.
BP1	N/A	BP1 is not applicable because this is not a missense variant.
BP2	Not assessed	No phase data were identified to assess BP2.
BP3	N/A	BP3 is not applicable because this variant is not an in-frame insertion or deletion in a repetitive region.
BP4	Met	Available computational evidence supports no impact on splicing: SpliceAI predicts no significant splice effect with a maximum delta score of 0.00, and no damaging computational evidence was identified for this synonymous variant.	spliceai
BP5	Not assessed	No alternate molecular explanation was identified that would allow assessment of BP5.
BP6	Not met	No reputable external classification source identifying this variant as benign was found; the variant is absent from ClinVar.	clinvar
BP7	Not met	This is a synonymous variant and SpliceAI predicts no significant splice impact with a maximum delta score of 0.00, but no conservation evidence was identified to complete BP7 assessment.	spliceai

Disclaimer: The content and results provided by LYFE Sciences are for research and educational purposes only and must not be used as a substitute for professional medical judgment, diagnosis, or treatment. Always consult a qualified healthcare professional before making any clinical decisions.