Classification rationale

PM2 VUS

ATR c.6680A>G

NM_001184.3:c.6680A>G (p.Asn2227Ser) is a missense variant in ATR that is absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2_moderate).¹ No functional data, case-control studies, segregation data, or de novo observations were identified for this variant. OncoKB classifies it as Unknown Oncogenic Effect. ClinVar reports it as Uncertain significance (1★, single submitter).² In silico predictors are equivocal: REVEL 0.545 (borderline), BayesDel -0.21413 (benign), SpliceAI max delta 0.00 (no splicing impact). This does not meet PP3 or BP4 thresholds.³ The only met ACMG criterion is PM2 at moderate strength (absent from population databases). No other pathogenic or benign criteria are met. Under generic ACMG/AMP 2015 combination rules (PMID:25741868), a single moderate criterion is insufficient for classification as likely pathogenic, and no benign criteria are met to offset it. The variant is classified as Uncertain Significance (VUS).⁴

PM2 → VUS

1 gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

2 clinvar ↗oncokb ↗

3 revelbayesdelspliceai ↗

4 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 · 1 applied · 22 assessed

Applied · 1

Strength Supporting Moderate Strong Very strong

✓

PM2 moderate Pathogenic

The variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes/genomes), and gnomAD-Canada v1.0 (genomes). This satisfies the PM2 criterion (allele frequency <0.1% in large population cohorts) for a rare missense variant in ATR.

gnomAD v2.1: absent (AC=nullAN=nullAF=null)

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

Assessed · not applied

Pathogenic

PS1 No evidence was identified that a different nucleotide change at this position resulting in the same amino acid substitution (p.Asn2227Ser) has been previously classified as pathogenic.

PS2 No data on de novo occurrence of this variant were identified.

PS3 No functional data were identified for NM_001184.3:c.6680A>G (p.Asn2227Ser) in OncoKB, the literature, or other curated sources.

PS4 No case-control studies or prevalence data comparing this variant in affected vs.

PM1 The variant (p.Asn2227Ser) is not located in a statistically significant mutational hotspot per cancerhotspots.org.

PM5 No pathogenic or likely pathogenic missense variants at the same amino acid residue (p.Asn2227) were identified in ClinVar or the candidate search.

PM6 No de novo observation (confirmed or unconfirmed) of this variant was identified.

PP1 No co-segregation data are available for this variant.

PP2 No HCI prior probability score or gene-specific missense constraint metric (e.g., missense Z-score, o/e ratio) is available for ATR in the case materials.

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

PP4 No phenotypic data for the proband or affected individuals carrying this variant are available in the case materials.

PP5 This variant is classified as Uncertain significance in ClinVar (ClinVarID 2624947) by a single clinical laboratory with review status 'criteria provided, single submitter' (1★).

Benign

BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada.

BS2 No observation of this variant in a homozygous or hemizygous state in healthy adults was identified.

BS3 No well-established functional studies showing no damaging effect of this variant were identified.

BS4 No family segregation data are available to demonstrate lack of co-segregation with disease.

BP1 While ATR loss-of-function is supported as a germline disease mechanism (pvs1_gene_context: lof_mechanism_supported=true), there is insufficient evidence to conclude that missense variants in ATR are not a disease mechanism.

BP2 No observation of this variant in trans with a known pathogenic variant in a fully penetrant dominant disorder.

BP4 In silico evidence is mixed and does not provide multiple consistent lines supporting no impact.

BP5 No alternate molecular cause for the observed phenotype was identified in the case materials.

BP6 This variant is classified as Uncertain significance in ClinVar (ClinVarID 2624947) by a single clinical laboratory (1★).

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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2624947)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.545. BayesDel score = -0.21413.

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

Triaged references · 5 PMIDs not cited in assessment

23619275 ↗ ACMG position statement on prenatal/preconception expanded carrier screening. CLINVAR

25730230 ↗ Expanded carrier screening in reproductive medicine-points to consider: a joint statement of the American College of Medical Genetics and Genomics, American College of Obstetricians and Gynecologists, National Society of Genetic Counselors, Perinatal Quality Foundation, and Society for Maternal-Fetal Medicine. CLINVAR

23037933 ↗ Including the initial newborn screening bloodspot collection device serial number on birth certificates: basis and recommendations from the Secretary of Health and Human Services' Advisory Committee on Heritable Disorders in Newborns and Children. CLINVAR

24022298 ↗ Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected]. CLINVAR

24394680 ↗ Parental permission for pilot newborn screening research: guidelines from the NBSTRN. CLINVAR