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 applied · 18 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PVS1
very strong
Pathogenic
Nonsense variant (p.Asp1821Ter) in ATR, where loss-of-function is an established disease mechanism for Seckel syndrome. The premature termination codon at position 1821 of 2645 resides well upstream of the last exon; nonsense-mediated decay is expected. Under ClinGen SVI PVS1 recommendations (PMC6185798), this qualifies for PVS1 at very strong evidence level.
Nonsense variant p.Asp1821Ter (NP_001175.2:p.(D1821*)) predicted to trigger nonsense-mediated decayATR loss-of-function is an established germline disease mechanism (Seckel syndrome type 1)Variant is not in the last exon
✓
PM2
moderate
Pathogenic
NM_001184.3:c.5459_5460insC is absent from gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with a rare pathogenic variant. Under generic ACMG/AMP 2015, absence from population databases supports PM2 at moderate strength.
gnomAD v2.1: absent (AF=0)gnomAD v4.1: absent (AF=0)gnomAD-Canada v1.0: absent (AF=0.0
Assessed · not applied
Pathogenic
PS2
No confirmed de novo occurrence with established maternity and paternity has been reported for NM_001184.3:c.5459_5460insC.
PS3
No variant-specific functional studies demonstrating a damaging effect on ATR protein function were identified.
PS4
No case-control study comparing the prevalence of this variant in affected versus unaffected individuals is available.
PM1
The variant does not lie in a statistically significant mutational hotspot or a well-characterized critical functional domain without benign variation, per cancerhotspots.org analysis.
PM6
No de novo observation (assumed or confirmed) has been reported for this variant.
PP1
No co-segregation data are available for this variant.
PP3
No in silico prediction tools (REVEL, BayesDel) provide scores for insertion variants.
PP4
No detailed patient phenotype information is available for individuals carrying this variant.
PP5
No reputable source (e.g., clinical diagnostic laboratory) has independently classified NM_001184.3:c.5459_5460insC.
Benign
BA1
The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.
BS1
The variant is absent from population databases.
BS2
The variant has not been observed in healthy adult individuals to satisfy BS2 criteria.
BS3
No variant-specific functional studies demonstrating no damaging effect on ATR protein function are available.
BS4
No family studies demonstrating lack of segregation between this variant and disease have been reported.
BP2
No observation of this variant in trans with a pathogenic ATR variant in a healthy individual, or in cis with a pathogenic variant, has been reported.
BP4
Multiple lines of computational evidence suggesting no impact are not satisfied.
BP5
No observation of this variant in a case where an alternative molecular basis for the disease has been identified.
BP6
No reputable source has classified this variant as benign or likely benign.
N/A · 8
PS1 · PM3 · PM4 · PM5 · PP2 · BP1 · BP3 · BP7
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