About ATR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATR c.1751A>G, p.(Asp584Gly)
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.
Words with a dotted underline have a short definition. Hover or tap them.
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
NM_001184.3:c.1751A>G is absent from large population databases including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). In the generic ACMG/AMP 2015 framework, absence from population databases supports pathogenicity at supporting strength when the variant is not observed in a large number of ethnically diverse individuals.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.11 (predicts benign, below the standard 0.5 threshold). BayesDel score is -0.208 (negative, predicts benign). While SpliceAI max delta is 0.33 (borderline above 0.2), the Pangolin splice loss score is -0.31 (predicts no splice-altering effect). The preponderance of in silico evidence supports a benign interpretation at supporting strength.
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.
gnomAD v4.1
gnomAD v2.1
Population frequency
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.330 maximum delta
Recorded SpliceAI maximum delta score: 0.330. Refer to the recorded PP3/BP4 rationale for interpretation.
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
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
26 criteria with recorded statuses: 2 met · 21 not met · 0 not assessed · 3 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_001184.3:c.1751A>G (p.Asp584Gly) is absent from all population databases including gnomAD v2.1, v4.1, and gnomAD-Canada, meeting PM2 at supporting strength.
Multiple computational predictors suggest a benign effect: REVEL score 0.11 and BayesDel score -0.208 both predict no deleterious impact, meeting BP4 at supporting benign strength.
SpliceAI max delta score is 0.33 (acceptor loss 0.33, donor loss 0.30), which is borderline above the 0.2 threshold, but Pangolin splice loss score of -0.31 predicts no splice-altering effect. The in silico consensus favors a neutral interpretation.
No functional data, no published cases, no ClinVar classifications, and no segregation data are available for this variant. All remaining pathogenic and benign criteria are not met.
With one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is balanced. The variant is classified as a Variant of Uncertain Significance (VUS) per ACMG/AMP 2015 combination rules.
No criteria match.
Met · 2
PM2 SupportingNM_001184.3:c.1751A>G is absent from large population databases including gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes). In the generic ACMG/AMP 2015 framework, absence from population databases supports pathogenicity at supporting strength when the variant is not observed in a large number of ethnically diverse individuals. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- Absent from gnomAD v4.1 (exomes)
- Absent from gnomAD-Canada v1.0 (genomes)
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.11 (predicts benign, below the standard 0.5 threshold). BayesDel score is -0.208 (negative, predicts benign). While SpliceAI max delta is 0.33 (borderline above 0.2), the Pangolin splice loss score is -0.31 (predicts no splice-altering effect). The preponderance of in silico evidence supports a benign interpretation at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.11 (predicts benign)
- BayesDel: -0.208077 (predicts benign)
- SpliceAI: max delta 0.33 (borderline
- Pangolin SL=-0.31 predicts no splice effect)
Still missing
- SpliceAI delta 0.33 is borderline
- RNA studies could definitively resolve any cryptic splice effect
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No alternative nucleotide change resulting in the same amino acid substitution (p.Asp584Gly) has been reported as pathogenic. The variant is absent from ClinVar, and no literature reports a different nucleotide change at this codon with an established pathogenic classification. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no entries for codon 584 of ATR
- No publications identified reporting a different nucleotide change at this position
Still missing
- No systematic search for all nucleotide changes at codon 584 beyond standard evidence sources
Sources
PS2 No de novo occurrence has been reported for this variant. No publications mention NM_001184.3:c.1751A>G, and no family studies with confirmed parentage are available. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no de novo submissions
- Zero publications identified across all evidence sources for this variant
Still missing
- No family studies or trio sequencing data available
PS3 No functional data exist for NM_001184.3:c.1751A>G (p.Asp584Gly). OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no variant-specific curated functional evidence. No publications with functional characterization were identified. The variant is absent from COSMIC and has not been studied in any experimental system. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence curated
- Absent from COSMIC (no somatic occurrence data)
- Zero publications identified for this variant
Still missing
- No experimental functional characterization of p.Asp584Gly has been performed
Sources
PS4 The variant has not been observed in any affected individuals. It is absent from ClinVar, absent from gnomAD, and absent from all publications. No case-control or odds-ratio analysis is possible for a variant with zero observations. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- v4.1
- and gnomAD-Canada
- Absent from ClinVar (no affected individuals reported)
- No published cases identified
Still missing
- No affected individuals have been reported
- prevalence in disease cohorts unknown
Sources
PM1 Residue Asp584 is not located in a statistically significant mutational hotspot (cancerhotspots.org negative). No evidence was identified that this specific residue lies within a well-characterized functional domain where missense variants are an established pathogenic mechanism for germline ATR-related disease. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- exact variant not listed
- No domain-level functional characterization specific to residue 584 identified in the literature
- OncoKB: no curated domain-level functional annotation for this residue
Still missing
- ATR domain architecture at residue 584 not systematically evaluated against known functional domains (FAT
- kinase
- etc.)
Sources
pvs1_gene_context
PM5 No pathogenic missense variant at the same amino acid residue (Asp584) has been identified. The PM5 candidate search returned zero comparators. ClinVar has no entries for any missense change at codon 584 of ATR. No literature reports describe a different pathogenic amino acid change at this position. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates
- mode 'unknown'
- not eligible for classic PM5
- ClinVar absent for all variants at codon 584
Still missing
- No systematic ClinVar search for all possible amino acid changes at residue 584 beyond automated harvesting
Sources
pm5_candidatesclinvar ↗
PM6 No de novo occurrence has been reported for this variant. No publications describe a de novo ATR c.1751A>G event with confirmed maternity and paternity. No ClinVar submissions assert de novo status. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no de novo assertions
- Zero publications identified
- no de novo reports
Still missing
- No trio or parent-offspring sequencing data available
Sources
PP1 No segregation data are available. The variant has not been identified in any family, and no co-segregation analysis with disease phenotype has been performed. Details ▾Hide ▴
Evidence considered
- No family studies or pedigrees available
- Variant absent from ClinVar
- no familial submissions
Still missing
- No segregation analysis possible without family data
Sources
PP2 While ATR loss of function is supported as a germline disease mechanism, there is insufficient evidence that ATR has a low rate of benign missense variation and that missense variants are a common mechanism of disease. Missense constraint metrics (e.g., gnomAD missense Z-score) were not provided, and the HCI prior score was not found. Details ▾Hide ▴
Evidence considered
- ATR LoF is supported as a germline disease mechanism (literature-based)
- No missense-specific constraint metrics available (HCI prior not found)
- Insufficient evidence that missense variants are a common mechanism for ATR-related disease
Still missing
- gnomAD missense constraint metrics (Z-score
- o/e) not evaluated
- No gene-specific PP2 framework from a VCEP/CSPEC
Sources
pvs1_gene_context
PP3 Multiple computational predictors do not support a deleterious effect. REVEL score is 0.11 (predicts benign), BayesDel score is -0.208 (predicts benign). SpliceAI max delta score is 0.33 (acceptor loss 0.33, donor loss 0.30), which is above the 0.2 threshold, but the Pangolin splice loss score is -0.31 (predicts no splice-altering effect). The preponderance of in silico evidence favors a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.11 (predicts benign
- below commonly used 0.5 threshold)
- BayesDel: -0.208077 (negative score
- predicts benign)
- SpliceAI: max delta 0.33 (DS_AL=0.33
- DS_DL=0.30
- borderline above 0.2)
- Pangolin: SG=0.0
- SL=-0.31 (predicts no splice-altering effect)
- HCI prior: not found
Still missing
- SpliceAI delta 0.33 is borderline
- RNA studies could resolve potential cryptic splice effect
Sources
PP4 No patient with this variant and a phenotype specific for ATR-related disease has been reported. The variant has not been observed in any individual, precluding phenotype-specificity assessment. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no phenotype data available
- No published cases with this variant
Still missing
- No clinical phenotype data available for this variant
Sources
PP5 The variant is absent from ClinVar. No reputable source has reported this variant as pathogenic. In the absence of any classification, PP5 cannot be applied. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no classification from any submitter
- No ClinVar variation ID exists for this variant
Sources
BA1 The variant is absent from gnomAD (allele frequency = 0). BA1 requires an allele frequency >5% (or >1% depending on framework) in population databases, which is not met when the variant is entirely absent. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF=0)
- gnomAD v4.1: absent (AF=0)
- gnomAD-Canada v1.0: absent (AF=0)
Sources
BS1 The variant is absent from gnomAD (allele frequency = 0). BS1 requires the allele frequency to be greater than expected for the disorder prevalence (typically >0.3% for rare dominant disorders in generic ACMG). A frequency of zero does not satisfy BS1; absence from population databases supports PM2, not BS1. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AF=0
- does not exceed BS1 threshold)
- gnomAD v4.1: absent (AF=0)
- gnomAD-Canada v1.0: absent (AF=0)
Sources
BS2 The variant has not been observed in any individual, healthy or affected. BS2 requires observation in a healthy adult individual for a fully penetrant disorder expected to manifest at an early age. Without any observations, BS2 cannot be evaluated. Details ▾Hide ▴
Evidence considered
- Variant absent from all population databases
- no healthy carriers identified
- No observation in any individual
- precluding BS2 application
Still missing
- No healthy control data available for this variant
Sources
BS3 No functional studies have been performed on this variant. BS3 requires well-established in vitro or in vivo functional studies demonstrating no damaging effect on protein function or splicing. No such studies exist for p.Asp584Gly. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional studies curated
- No publications with functional characterization of this variant
- No COSMIC somatic data suggestive of functional neutral effect
Still missing
- No experimental functional data exist for this variant
Sources
BS4 No segregation data are available for this variant. BS4 requires lack of segregation in affected family members. No families with this variant have been identified. Details ▾Hide ▴
Evidence considered
- No family studies available
- No co-segregation or lack-of-segregation data
Still missing
- No family/pedigree data available for segregation analysis
Sources
BP1 BP1 applies to missense variants in genes where truncating variants are the only known cause of disease. While ATR loss-of-function is supported as a germline disease mechanism, insufficient evidence exists to conclude that missense variants cannot also be pathogenic. No gene-specific framework restricts ATR pathogenicity exclusively to truncating variants. Details ▾Hide ▴
Evidence considered
- ATR LoF is a supported disease mechanism (literature-based)
- No evidence that missense variants are excluded as a disease mechanism for ATR
Still missing
- No comprehensive gene-level assessment of missense vs. truncating variant contribution to ATR-related disease
Sources
pvs1_gene_context
BP2 The variant has not been observed in any individual. BP2 requires observation in trans with a known pathogenic variant (for fully penetrant dominant disorders) or in cis with a pathogenic variant (for recessive disorders). No co-occurrence data are available. Details ▾Hide ▴
Evidence considered
- No observation of this variant in any individual
- No co-occurrence data with other pathogenic ATR variants
Still missing
- No phase or co-occurrence data available
Sources
BP5 No alternative molecular basis for disease has been identified in an individual carrying this variant. BP5 requires a case where an alternate cause of disease is found while this variant is also present, which has not been reported. Details ▾Hide ▴
Evidence considered
- No case identified where an alternate molecular cause co-occurs with this variant
Still missing
- No clinical cases available to evaluate alternative molecular diagnoses
BP6 The variant is absent from ClinVar. BP6 requires a reputable source to have recently reported the variant as benign. No such classification exists. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign classification from any submitter
Sources
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001184.3:c.1751A>G is a missense variant (p.Asp584Gly) and does not fall into any generic PVS1 null-variant bucket (nonsense, frameshift, or canonical ±1,2 splice consensus). The ClinGen SVI PVS1 framework (PMC6185798) does not apply to missense substitutions in the absence of a demonstrated effect on splicing at the RNA level. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution (c.1751A>G
- p.Asp584Gly)
- No canonical splice site involvement
- PVS1 variant assessment classifies as bucket 'other'
- apply_generic_pvs1_framework=false
Sources
BP7 N/ABP7 applies specifically to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_001184.3:c.1751A>G is a missense variant (p.Asp584Gly), not a synonymous variant. BP7 is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Variant is missense (c.1751A>G
- p.Asp584Gly)
- not synonymous
Sources
generic_acmg_combination_rules
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 classification framework (PMID:25741868). The established pathogenic criteria are PVS1, PS1–PS4, PM1–PM6, and PP1–PP5. No VCEP/CSPEC framework is available for ATR to define an extended PS5 criterion. Details ▾Hide ▴
Evidence considered
- Standard ACMG/AMP 2015 criteria do not include PS5
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- ATR
- Transcript
- NM_001184.3
- Coding (HGVS c.)
- NM_001184.3:c.1751A>G
- Protein (HGVS p.)
- NP_001175.2:p.(Asp584Gly)
- GRCh38
- chr3:142558758 T>C
- GRCh37
- chr3:142277600 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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ATR
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
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
Other predictors
- REVEL
- 0.110
- BayesDel
- -0.208
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product. REVEL score is 0.11 (predicts benign, below the standard 0.5 threshold). BayesDel score is -0.208 (negative, predicts benign). While SpliceAI max delta is 0.33 (borderline above 0.2), the Pangolin splice loss score is -0.31 (predicts no splice-altering effect). The preponderance of in silico evidence supports a benign interpretation at supporting strength. Details ▾Hide ▴
Evidence considered
- REVEL: 0.11 (predicts benign)
- BayesDel: -0.208077 (predicts benign)
- SpliceAI: max delta 0.33 (borderline
- Pangolin SL=-0.31 predicts no splice effect)
Still missing
- SpliceAI delta 0.33 is borderline
- RNA studies could definitively resolve any cryptic splice effect
Sources
PP3 Multiple computational predictors do not support a deleterious effect. REVEL score is 0.11 (predicts benign), BayesDel score is -0.208 (predicts benign). SpliceAI max delta score is 0.33 (acceptor loss 0.33, donor loss 0.30), which is above the 0.2 threshold, but the Pangolin splice loss score is -0.31 (predicts no splice-altering effect). The preponderance of in silico evidence favors a neutral effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.11 (predicts benign
- below commonly used 0.5 threshold)
- BayesDel: -0.208077 (negative score
- predicts benign)
- SpliceAI: max delta 0.33 (DS_AL=0.33
- DS_DL=0.30
- borderline above 0.2)
- Pangolin: SG=0.0
- SL=-0.31 (predicts no splice-altering effect)
- HCI prior: not found
Still missing
- SpliceAI delta 0.33 is borderline
- RNA studies could resolve potential cryptic splice effect
Sources
BP7 N/ABP7 applies specifically to synonymous (silent) variants for which splicing prediction algorithms predict no impact and the nucleotide is not highly conserved. NM_001184.3:c.1751A>G is a missense variant (p.Asp584Gly), not a synonymous variant. BP7 is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Variant is missense (c.1751A>G
- p.Asp584Gly)
- not synonymous
Sources
generic_acmg_combination_rules
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.33). REVEL score = 0.11. BayesDel score = -0.208077.
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 0.330
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
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/?term=NM_001184.3%3Ac.1751A%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-142277600-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-142558758-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-142558758-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001184.3%3Ac.1751…
- OncoKB ↗www.oncokb.org/gene/ATR/D584G
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATR+c.1751A%3EG
- Cancer hotspots ↗www.cancerhotspots.org/
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 possible splice impact for this variant (max delta score = 0.33). REVEL score = 0.11. BayesDel score = -0.208077.
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.