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ATRc.1316A>GUncertain significance
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Variant interpretation report

ATR c.1316A>G, p.(Asn439Ser)

NM_001184.3:c.1316A>G NP_001175.2:p.(Asn439Ser) View identifiers
Classification
Uncertain significance

Variant description:

No variant summary was recorded for this case.

Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.

Uncertain.The recorded classification is uncertain significance.

In plain language

Gene-level background from the recorded interpretation.

About ATR

No gene-level summary was recorded for this case.

LYFE Sciences is an AI system, and it can make mistakes. Criteria may be applied incorrectly, sources may be misread, and a confident-looking classification can still be wrong. Double-check every criterion and its underlying evidence before relying on any call.
01The reasoning

How it was classified

The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.

Recorded applied criteria

The applied criteria and their strengths are shown as assessed under the stated framework.

Pathogenic evidence criteria: 1 Benign evidence criteria: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting

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%.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

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.

Recorded classification: Uncertain significance

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.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

SpliceAI score
0.020 maximum delta

Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · BP4 → SpliceAI ↗
ClinVar submissions
Not recorded

A ClinVar laboratory submission summary was not recorded.

Context only ClinVar ↗
Functional evidence
Statement recorded

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.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
No matching record reported

This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.

Context only
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under Not recorded, with the data and sources behind each one.

29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

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.

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.

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.

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.

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).

Met · 2

PM2 SupportingThis 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%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD v2.1 (AF=0)
  • v4.1 (AF=0)
  • and Canada v1.0 (AF=0).
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.042 (benign range)
  • BayesDel -0.769573 (benign range)
  • SpliceAI max delta 0.02 (no splice impact predicted).
Sources
revelbayesdelspliceai ↗

Not met · 22 · evaluated, threshold not reached

PS1 No alternate nucleotide change at c.1316 resulting in the same N439S amino acid substitution has been reported as pathogenic. The variant is absent from ClinVar and the literature. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic alternate nucleotide change at this residue identified.
Still missing
  • No pathogenicity data for alternate nucleotide changes at c.1316.
Sources
clinvar ↗
PS2 No de novo occurrence data with confirmed maternity and paternity testing is available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo data in ClinVar or literature.
Still missing
  • No parental testing or de novo reports identified.
PS3 No variant-specific functional data or systematic range characterization is available for N439S in ATR. OncoKB reports unknown oncogenic effect with no curated functional evidence. No experimental studies were identified in the literature that directly tested this variant or a systematically characterized range containing it. Details ▾Hide ▴
Evidence considered
  • OncoKB classification: Unknown Oncogenic Effect. No functional studies identified for N439S in ATR.
Still missing
  • No functional assays performed for N439S
  • no systematic range characterization covering residue 439.
Sources
oncokb ↗
PS4 No case-control or cohort prevalence data comparing affected versus unaffected individuals is available for this variant. Details ▾Hide ▴
Evidence considered
  • No case-control data in ClinVar
  • COSMIC
  • or literature.
Still missing
  • No affected-vs-unaffected prevalence data.
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. Details ▾Hide ▴
Evidence considered
  • Not in a cancerhotspots.org hotspot
  • no domain-level functional annotation specific to N439.
Still missing
  • No functional domain annotation mapping N439 to a characterized critical domain.
PM5 No different pathogenic missense variant at the same amino acid residue (N439) has been identified. PM5 candidate harvesting found no comparator variants at this residue in ClinVar. Details ▾Hide ▴
Evidence considered
  • No pathogenic missense variants at N439 in ClinVar
  • PM5 candidate search returned zero same-residue candidates.
Still missing
  • No alternate missense change at N439 with pathogenic classification.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo occurrence data with confirmed maternity and paternity testing is available for this variant. Details ▾Hide ▴
Evidence considered
  • No de novo reports identified.
Still missing
  • No parental testing or de novo occurrence data.
PP1 No segregation data is available for this variant in affected families. Details ▾Hide ▴
Evidence considered
  • No segregation analysis reported.
Still missing
  • No family studies or cosegregation data.
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. Insufficient evidence to apply PP2. Details ▾Hide ▴
Evidence considered
  • HCI prior not found for this variant
  • no missense constraint data available.
Still missing
  • No missense constraint (Z-score) or HCI prior data for ATR.
PP3 In silico tools do not support a deleterious prediction. REVEL score is 0.042 (well below clinical pathogenic threshold), BayesDel score is -0.769573 (benign range), and SpliceAI max delta is 0.02 (no predicted splice alteration). All available tools point toward a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.042 (low)
  • BayesDel -0.769573 (benign)
  • SpliceAI max delta 0.02 (no splice impact).
Sources
revelbayesdelspliceai ↗
PP4 No phenotype specificity data is available. The variant has not been reported in clinically characterized patients to allow assessment of phenotypic specificity. Details ▾Hide ▴
Evidence considered
  • No phenotype data available.
Still missing
  • No patient phenotype data for this variant.
PP5 No reputable source has reported this variant as pathogenic. The variant has no ClinVar entries and is not cited in the literature. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar and literature.
Still missing
  • No diagnostic laboratory or expert panel reports.
Sources
clinvar ↗
BA1 This variant is absent from all population databases (gnomAD v2.1, v4.1, and gnomAD-Canada). It does not meet the BA1 threshold of allele frequency >1%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • AF=0 in all population datasets.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS1 This variant is absent from all population databases. It does not meet the BS1 threshold of allele frequency >0.3%. Details ▾Hide ▴
Evidence considered
  • Absent from gnomAD
  • AF=0 in all population datasets.
Sources
gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗
BS2 No data on observation of this variant in healthy adult individuals is available. The variant is absent from gnomAD, precluding assessment of homozygous or high-frequency observations in controls. Details ▾Hide ▴
Evidence considered
  • No healthy control observations available.
Still missing
  • No data on variant in healthy adults.
BS3 No functional studies demonstrating a neutral or benign effect on protein function are available for N439S in ATR. Details ▾Hide ▴
Evidence considered
  • No functional studies showing no deleterious effect for N439S.
Still missing
  • No functional data available for N439S.
Sources
oncokb ↗
BS4 No segregation data is available to demonstrate lack of cosegregation with disease in affected families. Details ▾Hide ▴
Evidence considered
  • No segregation data available.
Still missing
  • No family cosegregation data.
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. The available gene-level literature does not support restricting pathogenesis solely to truncating variants. Details ▾Hide ▴
Evidence considered
  • ATR LoF mechanism supported
  • but insufficient evidence that missense variants cannot cause disease.
Still missing
  • No evidence that ATR disease is exclusively caused by truncating variants.
Sources
pvs1_gene_context
BP2 No observations of this variant in trans with a known pathogenic ATR variant are available. Details ▾Hide ▴
Evidence considered
  • No in-trans observations reported.
Still missing
  • No phase data or trans configuration reports.
BP5 No case in which an alternative molecular basis for disease was identified while this variant was also present is available. Details ▾Hide ▴
Evidence considered
  • No alternative molecular basis data available.
Still missing
  • No cases with alternate molecular diagnosis identified.
BP6 No reputable source has reported this variant as benign. The variant has no ClinVar entries. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no benign assertion from any reputable source.
Still missing
  • No diagnostic laboratory or expert panel benign classifications.
Sources
clinvar ↗
PS5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar and the literature. Details ▾Hide ▴
Evidence considered
  • Variant absent from ClinVar
  • no pathogenic assertion from any reputable source.
Still missing
  • No diagnostic laboratory submissions or expert panel classifications.
Sources
clinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (NM_001184.3:c.1316A>G, p.Asn439Ser) that does not fall into the ClinGen SVI PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants. PVS1 does not apply to missense substitutions under the generic ACMG/AMP framework. Details ▾Hide ▴
Evidence considered
  • Variant type is missense
  • not eligible for PVS1 under generic framework per ClinGen SVI recommendations (PMC6185798).
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ATrivially not applicable: no variant-specific data for recessive/trans configuration assessment is available. Details ▾Hide ▴

No further detail was recorded.

PM4 N/ATrivially not applicable: this is a missense substitution, not a non-frameshift indel or stop-loss variant. Details ▾Hide ▴

No further detail was recorded.

BP3 N/ATrivially not applicable: this is a missense substitution, not an in-frame indel in a repetitive region. Details ▾Hide ▴

No further detail was recorded.

BP7 N/AThis is a missense variant (c.1316A>G, p.Asn439Ser). BP7 applies only to synonymous/silent variants with no predicted splice impact. Not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
  • Variant type is missense
  • BP7 is for synonymous variants only.

Identifiers

Gene
ATR
Transcript
NM_001184.3
Coding (HGVS c.)
NM_001184.3:c.1316A>G
Protein (HGVS p.)
NP_001175.2:p.(Asn439Ser)
GRCh38
chr3:142561276 T>C
GRCh37
chr3:142280118 T>C

Gene diagram

Every interpreted variant in ATR, mapped onto the exon structure of NM_001184.3. Select a row to find it on the plot.

ATRNM_001184.3
Fetching transcript structure from UCSC…
gnomAD v4.1 Allele count data not recorded
gnomAD v2.1 Allele count data not recorded
gnomAD-Canada v1.0 Allele count data not recorded

Statements

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +120 bp
0.000
SpliceAI acceptor gainat +145 bp
0.020
SpliceAI donor lossat -52 bp
0.010
SpliceAI donor gainat -28 bp
0.000
Pangolin splice lossmagnitude shown
-0.010
Pangolin splice gain
0.040

Other predictors

REVEL
0.042
BayesDel
-0.770

How the predictions were used

BP4 SupportingMultiple 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. Details ▾Hide ▴
Evidence considered
  • REVEL 0.042 (benign range)
  • BayesDel -0.769573 (benign range)
  • SpliceAI max delta 0.02 (no splice impact predicted).
Sources
revelbayesdelspliceai ↗
PP3 In silico tools do not support a deleterious prediction. REVEL score is 0.042 (well below clinical pathogenic threshold), BayesDel score is -0.769573 (benign range), and SpliceAI max delta is 0.02 (no predicted splice alteration). All available tools point toward a benign effect. Details ▾Hide ▴
Evidence considered
  • REVEL 0.042 (low)
  • BayesDel -0.769573 (benign)
  • SpliceAI max delta 0.02 (no splice impact).
Sources
revelbayesdelspliceai ↗
BP7 N/AThis is a missense variant (c.1316A>G, p.Asn439Ser). BP7 applies only to synonymous/silent variants with no predicted splice impact. Not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
  • Variant type is missense
  • BP7 is for synonymous variants only.

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.042. BayesDel score = -0.769573.

0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 Captured gnomAD v4.1 source record Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.020 Open source ↗
ClinVar Captured ClinVar source record Open source ↗
COSMIC Captured COSMIC source record Open source ↗
Cancer hotspots Captured Cancer Hotspots source record Open source ↗
OncoKB Captured OncoKB source record Open source ↗

All source links

Statements for reports

The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.

gnomAD v4.1

Absent from gnomAD v4.1.

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant is absent from ClinVar.

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 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.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.