Classification rationale

PM2 BP4 VUS

ATR c.2112G>T

NM_001184.3:c.2112G>T (p.Lys704Asn) in ATR is a missense variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_moderate).¹ Multiple in silico predictors support a benign effect: REVEL score 0.15, BayesDel score -0.360, and SpliceAI max delta 0.16 indicate no significant impact on protein function or splicing (BP4_supporting).² This variant is absent from ClinVar with no functional studies, segregation data, de novo reports, or case-control evidence available. The evidence profile consists of one pathogenic moderate criterion (PM2) and one benign supporting criterion (BP4), resulting in a classification of Uncertain Significance under the generic ACMG/AMP 2015 framework (PMID:25741868).³

PM2 + BP4 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 revelbayesdelspliceai ↗

3 generic_acmg_combination_rulesclinvar ↗

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 moderate Pathogenic

This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold of allele frequency < 0.1% in all population databases under the generic ACMG/AMP framework.

gnomAD v2.1: absent (AF nullAC null)gnomAD v4.1: absent (AF null

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP4 supporting Benign

Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.15 (consistent with benign), BayesDel score is -0.360 (consistent with benign), and SpliceAI max delta score is 0.16 (no significant splice alteration).

REVEL: 0.15 (below 0.5 thresholdconsistent with benign)BayesDel: -0.360 (below pathogenic threshold

spliceai ↗

Assessed · not applied

Pathogenic

PS1 No alternate nucleotide change at the same position (c.2112) resulting in the same amino acid substitution (Lys704Asn) has been identified as pathogenic in ClinVar or the literature.

PS2 No de novo data available for this variant.

PS3 No functional studies have been identified for NM_001184.3:c.2112G>T (p.Lys704Asn) or a systematically characterized range that includes this position.

PS4 No case-control or cohort enrichment data available for this variant.

PM1 Position 704 does not fall within a statistically significant mutational hotspot (cancerhotspots.org negative) and no evidence was identified characterizing this residue as part of a critical functional domain with established pathogenic enrichment.

PM5 No pathogenic missense variant at the same residue (Lys704) has been identified in ClinVar.

PM6 No de novo data available for this variant.

PP1 No cosegregation data available for this variant.

PP2 No evidence was provided in the evidence brief demonstrating that ATR has a low rate of benign missense variation (e.g., missense Z-score, missense constraint metrics).

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

PP4 No patient phenotype or family history data are available for assessment.

PP5 This variant is absent from ClinVar.

Benign

BA1 This variant is absent from gnomAD population databases.

BS1 This variant is absent from gnomAD population databases.

BS2 No data are available regarding observation of this variant in healthy adults with full penetrance expected.

BS3 No in vitro or in vivo functional studies have been identified that demonstrate no damaging effect for NM_001184.3:c.2112G>T (p.Lys704Asn).

BS4 No segregation data are available to assess lack of segregation with disease in affected family members.

BP1 No evidence demonstrates that ATR is a gene for which primarily truncating variants cause disease and missense variants are benign.

BP2 No phasing data are available.

BP5 No data are available regarding an alternate molecular basis for disease in a case harboring this variant.

BP6 This variant is absent from ClinVar.

N/A · 5 PVS1 · PM3 · PM4 · BP3 · 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 = 0.16). REVEL score = 0.15. BayesDel score = -0.360396.

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