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ATR
Final classification
VUS
ATR c.1316A>G · p.Asn439Ser
ATR

This missense variant (NM_001184.3:c.1316A>G, p.Asn439Ser) in ATR is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with PM2 at supporting level.

Gene
ATR
Transcript
NM_001184.3
HGVS · transcript:coding
NM_001184.3:c.1316A>G
Consequence
N/A
GRCh38
chr3:142561276 T>C
GRCh37
chr3:142280118 T>C
Basis 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.
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.1316A>G

This missense variant (NM_001184.3:c.1316A>G, p.Asn439Ser) in ATR is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada v1.0, consistent with PM2 at supporting level.1 Multiple in silico tools predict a benign effect: REVEL score of 0.042, BayesDel score of -0.769573, and SpliceAI max delta of 0.02 (no predicted splice alteration), consistent with BP4 at supporting benign level.2 The variant is absent from ClinVar with no prior classifications, no COSMIC entries, no hotspot association, and no variant-specific functional data in OncoKB or the literature. No variant-specific publications were identified.3 PVS1 is not applicable as this is a missense variant; it does not fall into the null-variant buckets defined by the ClinGen SVI PVS1 framework.4 Overall, one supporting criterion toward pathogenicity (PM2) and one supporting benign criterion (BP4) are met. This does not satisfy the combination thresholds for Likely Pathogenic (≥2 supporting) or Likely Benign (≥2 supporting benign) under the generic ACMG/AMP 2015 classification rules. The variant is classified as a Variant of Uncertain Significance (VUS).5

PM2 + BP4 VUS
2 revelbayesdelspliceai ↗
4 pvs1_generic_framework ↗pvs1_variant_assessment
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
This variant is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). Allele frequency is 0 in all population databases, meeting the PM2 threshold of <0.1%.
Absent from gnomAD v2.1 (AF=0)v4.1 (AF=0)and Canada v1.0 (AF=0).
BP4 supporting Benign
Multiple in silico tools predict no significant impact on protein function or splicing. REVEL score is 0.042 (well below clinical pathogenic threshold), BayesDel score is -0.769573 (benign range), and SpliceAI max delta score is 0.02 (no predicted splice alteration at canonical sites). All available computational evidence supports a benign effect.
REVEL 0.042 (benign range)BayesDel -0.769573 (benign range)SpliceAI max delta 0.02 (no splice impact predicted).
Assessed · not applied
Pathogenic
PS1 No alternate nucleotide change at c.1316 resulting in the same N439S amino acid substitution has been reported as pathogenic.
PS2 No de novo occurrence data with confirmed maternity and paternity testing is available for this variant.
PS3 No variant-specific functional data or systematic range characterization is available for N439S in ATR.
PS4 No case-control or cohort prevalence data comparing affected versus unaffected individuals is available for this variant.
PM1 The N439 residue does not lie in a statistically significant hotspot on cancerhotspots.org, and no functional domain characterization was identified in the available evidence that specifically defines N439 as situated within a well-characterized critical functional domain.
PM5 No different pathogenic missense variant at the same amino acid residue (N439) has been identified.
PM6 No de novo occurrence data with confirmed maternity and paternity testing is available for this variant.
PP1 No segregation data is available for this variant in affected families.
PP2 No HCI missense constraint prior data is available for this gene-variant pair, and no gene-level missense constraint (Z-score) data was retrieved.
PP3 In silico tools do not support a deleterious prediction.
PP4 No phenotype specificity data is available.
PP5 No reputable source has reported this variant as pathogenic.
Benign
BA1 This variant is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada).
BS1 This variant is absent from all population databases.
BS2 No data on observation of this variant in healthy adult individuals is available.
BS3 No functional studies demonstrating a neutral or benign effect on protein function are available for N439S in ATR.
BS4 No segregation data is available to demonstrate lack of cosegregation with disease in affected families.
BP1 Although ATR loss-of-function is supported as a germline disease mechanism by targeted literature review, there is insufficient evidence to establish that truncating variants are the only or primary mechanism of ATR-related disease.
BP2 No observations of this variant in trans with a known pathogenic ATR variant are available.
BP5 No case in which an alternative molecular basis for disease was identified while this variant was also present is available.
BP6 No reputable source has reported this variant as benign.
N/A · 5 PVS1 · PM3 · PM4 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1 screenshot
gnomAD v4.1
gnomAD v2.1 screenshot
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.
ClinVar screenshot
ClinVar
This variant is absent from ClinVar.
SpliceAI screenshot
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.042. BayesDel score = -0.769573.
Functional / OncoKB screenshot
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 screenshot
COSMIC
Cancer hotspots screenshot
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
8Sources
ClinVar
gnomAD v2.1
gnomAD v4.1
gnomAD-Canada
SpliceAI
OncoKB
COSMIC
Cancer hotspots