NM_001184.3:c.1751A>G (p.Asp584Gly) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.1 Multiple computational predictors suggest a benign effect: REVEL score 0.11 and BayesDel score -0.208 both predict no deleterious impact, meeting BP4 at supporting benign strength.2 SpliceAI max delta score is 0.33 (acceptor loss 0.33, donor loss 0.30), which is borderline above the 0.2 threshold, but Pangolin splice loss score of -0.31 predicts no splice-altering effect. The in silico consensus favors a neutral interpretation.3 No functional data, no published cases, no ClinVar classifications, and no segregation data are available for this variant. All remaining pathogenic and benign criteria are not met.4 With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced. The variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules.5
ATR
Final classification
VUS
ATR c.1751A>G · p.Asp584Gly
ATR
NM_001184.3:c.1751A>G (p.Asp584Gly) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting benign; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
ATR c.1751A>G
PM2 + BP4
→
VUS
2
revelbayesdel
5
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 · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_001184.3:c.1751A>G is absent from large population databases including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). In the generic ACMG/AMP 2015 framework, absence from population databases supports pathogenicity at supporting strength when the variant is not observed in a large number of ethnically diverse individuals.
Absent from gnomAD v2.1 (exomes)Absent from gnomAD v4.1 (exomes)Absent from gnomAD-Canada v1.0 (genomes)
✓
BP4
supporting
Benign
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.11 (predicts benign, below the standard 0.5 threshold). BayesDel score is -0.208 (negative, predicts benign). While SpliceAI max delta is 0.33 (borderline above 0.2), the Pangolin splice loss score is -0.31 (predicts no splice-altering effect). The preponderance of in silico evidence supports a benign interpretation at supporting strength.
REVEL: 0.11 (predicts benign)BayesDel: -0.208077 (predicts benign)SpliceAI: max delta 0.33 (borderline
Assessed · not applied
Pathogenic
PS1
No alternative nucleotide change resulting in the same amino acid substitution (p.Asp584Gly) has been reported as pathogenic.
PS2
No de novo occurrence has been reported for this variant.
PS3
No functional data exist for NM_001184.3:c.1751A>G (p.Asp584Gly).
PS4
The variant has not been observed in any affected individuals.
PM1
Residue Asp584 is not located in a statistically significant mutational hotspot (cancerhotspots.org negative).
PM5
No pathogenic missense variant at the same amino acid residue (Asp584) has been identified.
PM6
No de novo occurrence has been reported for this variant.
PP1
No segregation data are available.
PP2
While ATR loss of function is supported as a germline disease mechanism, there is insufficient evidence that ATR has a low rate of benign missense variation and that missense variants are a common mechanism of disease.
PP3
Multiple computational predictors do not support a deleterious effect.
PP4
No patient with this variant and a phenotype specific for ATR-related disease has been reported.
PP5
The variant is absent from ClinVar.
Benign
BA1
The variant is absent from gnomAD (allele frequency = 0).
BS1
The variant is absent from gnomAD (allele frequency = 0).
BS2
The variant has not been observed in any individual, healthy or affected.
BS3
No functional studies have been performed on this variant.
BS4
No segregation data are available for this variant.
BP1
BP1 applies to missense variants in genes where truncating variants are the only known cause of disease.
BP2
The variant has not been observed in any individual.
BP5
No alternative molecular basis for disease has been identified in an individual carrying this variant.
BP6
The variant is absent from ClinVar.
N/A · 2
PVS1 · 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
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 possible splice impact for this variant (max delta score = 0.33). REVEL score = 0.11. BayesDel score = -0.208077.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATR, a tumor suppressor involved in DNA damage repair, is mutated in various cancer types.
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