Classification rationale

PM2 BP4 VUS

ATR c.2804A>C

PM2 (supporting): NM_001184.3:c.2804A>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare variant not observed in population databases.¹ BP4 (supporting): Multiple in silico predictors do not support a deleterious effect. SpliceAI max delta is 0.17 (no predicted splicing impact). BayesDel score is 0.216 (below deleterious threshold). REVEL score is 0.52 (indeterminate).² Classification: Uncertain Significance (VUS). One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in equivocal evidence. No other criteria were met in either the pathogenic or benign direction.³

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 spliceai ↗revelbayesdel

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 · 20 assessed

Applied · 2

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting Pathogenic

NM_001184.3:c.2804A>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold for absence from population databases (<0.1%).

Absent from gnomAD v2.1absent from gnomAD v4.1absent from gnomAD-Canada v1.0

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence suggest no deleterious impact. SpliceAI predicts no significant splicing effect (max delta score 0.17, below 0.2 threshold). BayesDel score is 0.216, below the typical deleterious threshold. REVEL score is 0.52 (indeterminate, does not support a pathogenic classification). The aggregate in silico evidence does not support a damaging effect on the gene product.

SpliceAI max delta 0.17 (no splicing impact)BayesDel 0.216 (low/benign range)REVEL 0.52 (indeterminate)

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No different pathogenic missense variant at the same amino acid position (Gln935) has been reported in ClinVar or the literature.

PS2 No de novo data are available for this variant.

PS3 No variant-specific functional data are available.

PS4 No case-control or prevalence data are available for this variant.

PM1 Position 935 in ATR lies in the N-terminal region of the protein, outside the characterized C-terminal kinase domain (PIKK domain, approximately residues 2300–2600).

PM6 No de novo reports are available.

PP1 No segregation data are available.

PP2 PP2 applies when missense variation is a common disease mechanism and the gene has a low rate of benign missense variation.

PP3 Multiple lines of computational evidence do not support a deleterious effect.

PP4 No phenotype or family history data are available for the proband.

PP5 This variant is absent from ClinVar.

Benign

BA1 BA1 requires an allele frequency >1% in a population database.

BS1 BS1 requires an allele frequency >0.3% in a population database.

BS2 BS2 requires observation of the variant in healthy adults in a homozygous state, or in trans with a pathogenic variant with full penetrance expected early in life.

BS3 No functional studies demonstrating a benign effect for this variant are available.

BS4 No segregation data showing lack of co-segregation with disease are available.

BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants are known to cause disease.

BP2 BP2 requires observation of the variant in trans with a known pathogenic variant in a gene associated with a fully penetrant recessive disorder.

BP5 BP5 requires the variant to be observed in a case with an alternate molecular basis for disease.

BP6 This variant is absent from ClinVar.

N/A · 3 PVS1 · PM5 · 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

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant is absent from ClinVar.

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). REVEL score = 0.52. BayesDel score = 0.216019.

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots