NM_001184.3:c.5459_5460insC (p.Asp1821Ter) is a nonsense variant in ATR, where loss-of-function is an established mechanism for Seckel syndrome type 1. The premature termination codon at position 1821 of 2645 is expected to trigger nonsense-mediated decay, satisfying PVS1 at very strong evidence level under ClinGen SVI PVS1 recommendations (PMC6185798).1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, supporting PM2 at moderate evidence level.2 No benign criteria are met. BA1 and BS1 are not satisfied (allele frequency 0%). BS2, BS3, BS4, BP2, BP4, BP5, and BP6 are not met or not assessed due to insufficient data. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), one very strong criterion (PVS1) plus one moderate criterion (PM2) supports a Likely Pathogenic classification.3
ATR
Final classification
Likely Pathogenic
ATR c.5459_5460insC · p.Asp1821Ter
ATR
NM_001184.3:c.5459_5460insC (p.Asp1821Ter) is a nonsense variant in ATR, where loss-of-function is an established mechanism for Seckel syndrome type 1. The premature termination codon at position 1821 of 2645 is expected to trigger nonsense-mediated decay, satisfying PVS1 at very strong evidence level under ClinGen SVI PVS1 recommendations (PMC6185798).
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 moderate; combination = 1 very strong + 1 moderate, which maps to Likely Pathogenic.
Classification rationale
PVS1PM2
Likely Pathogenic
ATR c.5459_5460insC
PVS1 + PM2
→
Likely Pathogenic
1
pvs1_generic_framework ↗pvs1_gene_contextpvs1_variant_assessment
3
generic_acmg_combination_rules
Gene diagram
· NM_001184.3 · variants mapped to exon structure
ATR
NM_001184.3
Fetching transcript structure from UCSC…
Applied criteria · 2 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports pathogenic
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
0 hom
Not observed in any ancestry group.
gnomAD v2.1
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00).
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.
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.
Sources & reference links
Triaged references · 2 PMIDs not cited in assessment
15282542 ↗
ATR functions as a gene dosage-dependent tumor suppressor on a mismatch repair-deficient background.
ONCOKB