About ATR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATR c.2804A>C, p.(Gln935Pro)
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.2804A>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold for absence from population databases (<0.1%).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no deleterious impact. SpliceAI predicts no significant splicing effect (max delta score 0.17, below 0.2 threshold). BayesDel score is 0.216, below the typical deleterious threshold. REVEL score is 0.52 (indeterminate, does not support a pathogenic classification). The aggregate in silico evidence does not support a damaging effect on the gene product.
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; 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
0.170 maximum delta
Recorded SpliceAI maximum delta score: 0.170. 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
PM2 (supporting): NM_001184.3:c.2804A>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with a rare variant not observed in population databases.
BP4 (supporting): Multiple in silico predictors do not support a deleterious effect. SpliceAI max delta is 0.17 (no predicted splicing impact). BayesDel score is 0.216 (below deleterious threshold). REVEL score is 0.52 (indeterminate).
Classification: Uncertain Significance (VUS). One supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4) result in equivocal evidence. No other criteria were met in either the pathogenic or benign direction.
No criteria match.
Met · 2
PM2 SupportingNM_001184.3:c.2804A>C is absent from gnomAD v2.1 (exomes), gnomAD v4.1 (exomes), and gnomAD-Canada v1.0 (genomes), meeting the PM2 threshold for absence from population databases (<0.1%). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1
- absent from gnomAD v4.1
- absent from gnomAD-Canada v1.0
Sources
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact. SpliceAI predicts no significant splicing effect (max delta score 0.17, below 0.2 threshold). BayesDel score is 0.216, below the typical deleterious threshold. REVEL score is 0.52 (indeterminate, does not support a pathogenic classification). The aggregate in silico evidence does not support a damaging effect on the gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.17 (no splicing impact)
- BayesDel 0.216 (low/benign range)
- REVEL 0.52 (indeterminate)
Sources
Not met · 21 · evaluated, threshold not reached
PS1 No different pathogenic missense variant at the same amino acid position (Gln935) has been reported in ClinVar or the literature. PS1 requires a different nucleotide change at the same codon resulting in the same amino acid change, or evidence of a different pathogenic missense at the same codon. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no same-codon pathogenic comparator identified
Still missing
- No literature search returned same-codon variants
Sources
PS2 No de novo data are available for this variant. Neither ClinVar submissions nor the literature search returned any de novo reports for NM_001184.3:c.2804A>C. Details ▾Hide ▴
Evidence considered
- No de novo observations in ClinVar or literature
Still missing
- No parental testing data available
PS3 No variant-specific functional data are available. OncoKB classifies this variant as Unknown Oncogenic Effect with no curated functional evidence. No publications with experimental functional characterization of NM_001184.3:c.2804A>C were identified in the literature search. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional studies identified
Still missing
- No functional studies testing Q935P or systematic characterization of residue range including position 935
Sources
PS4 No case-control or prevalence data are available for this variant. The variant is absent from ClinVar and has not been reported in any clinical case series or cohort studies. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no case reports or cohort studies identified
Still missing
- No affected vs. control comparison data
Sources
PM1 Position 935 in ATR lies in the N-terminal region of the protein, outside the characterized C-terminal kinase domain (PIKK domain, approximately residues 2300–2600). Cancerhotspots.org does not identify this residue as a statistically significant mutational hotspot. No domain-level functional characterization specifically implicating residue 935 in a critical functional domain was identified. Details ▾Hide ▴
Evidence considered
- Not in a cancerhotspots.org hotspot
- position 935 is N-terminal to the ATR kinase domain
- no domain-specific functional evidence for this residue
Still missing
- No ClinGen CSPEC/VCEP domain specification for ATR available
PM6 No de novo reports are available. The literature search returned zero PMIDs mentioning this variant, and ClinVar has no submissions for this variant. PM6 requires a confirmed de novo observation with maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar or literature
Still missing
- No parental testing data
PP1 No segregation data are available. No family studies including this variant have been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No co-segregation data available
Still missing
- No family studies available
PP2 PP2 applies when missense variation is a common disease mechanism and the gene has a low rate of benign missense variation. ATR has a relatively high background rate of missense variation in population databases and no ClinGen CSPEC/VCEP specification for missense constraint is available. Insufficient evidence to assert that missense variants in ATR meet the PP2 threshold under generic ACMG. Details ▾Hide ▴
Evidence considered
- No gene-specific missense constraint metric available
- HCI prior not found for this variant
Still missing
- No ATR-specific missense constraint Z-score or CSPEC guidance
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.52 (indeterminate, below typical pathogenic threshold of 0.75). BayesDel score is 0.216 (below typical deleterious threshold). SpliceAI max delta is 0.17 (no predicted splicing impact, below 0.2 threshold). Taken together, these in silico predictors do not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.52 (indeterminate)
- BayesDel 0.216 (low)
- SpliceAI max delta 0.17 (no splicing impact)
Sources
PP4 No phenotype or family history data are available for the proband. PP4 requires that the patient phenotype or family history is highly specific for the disease associated with the gene. Details ▾Hide ▴
Evidence considered
- No patient phenotype data available for assessment
Still missing
- Patient phenotype not provided
PP5 This variant is absent from ClinVar. No expert panel or reputable source has classified this variant as pathogenic or likely pathogenic. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no expert panel classification available
Sources
BA1 BA1 requires an allele frequency >1% in a population database. NM_001184.3:c.2804A>C is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, far below the BA1 threshold. Details ▾Hide ▴
BS1 BS1 requires an allele frequency >0.3% in a population database. NM_001184.3:c.2804A>C is absent from all gnomAD datasets, far below the BS1 threshold. Details ▾Hide ▴
BS2 BS2 requires observation of the variant in healthy adults in a homozygous state, or in trans with a pathogenic variant with full penetrance expected early in life. No such observations are available for this variant. Details ▾Hide ▴
Evidence considered
- No homozygous or compound heterozygous observations in control populations
Still missing
- No homozygote data available
BS3 No functional studies demonstrating a benign effect for this variant are available. No experimental characterization of p.Gln935Pro or systematic functional assessment of the region including residue 935 has been reported. Details ▾Hide ▴
Evidence considered
- No functional studies showing normal/benign protein function
Still missing
- No functional characterization of Q935P
BS4 No segregation data showing lack of co-segregation with disease are available. BS4 requires observation of the variant in a family member without the disease phenotype. Details ▾Hide ▴
Evidence considered
- No segregation data available
Still missing
- No family studies available
BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants are known to cause disease. While ATR loss of function is a supported disease mechanism, there is insufficient evidence to assert that missense variants in ATR are categorically benign. No ClinGen CSPEC/VCEP specification exists to apply BP1 to ATR missense variants. Details ▾Hide ▴
Evidence considered
- ATR LoF mechanism supported but missense pathogenicity not excluded
- no CSPEC/VCEP BP1 rule for ATR
Still missing
- No VCEP specification for BP1 applicability to ATR
Sources
pvs1_gene_context
BP2 BP2 requires observation of the variant in trans with a known pathogenic variant in a gene associated with a fully penetrant recessive disorder. No such observation is available. ATR-associated disease is not established as a recessive disorder with full penetrance expected early in life. Details ▾Hide ▴
Evidence considered
- Not observed in trans with a pathogenic ATR variant
Still missing
- Inheritance pattern of ATR-related disease not fully established
BP5 BP5 requires the variant to be observed in a case with an alternate molecular basis for disease. No such observation has been reported for this variant. Details ▾Hide ▴
Evidence considered
- Not reported in a case with an alternate molecular cause
BP6 This variant is absent from ClinVar. No expert panel or reputable source has classified this variant as benign or likely benign. BP6 cannot be applied without a trusted source classification. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar
- no benign/likely benign classification available
Sources
PS5 PS5 requires two or more independent sources reporting the variant in affected individuals. No sources — ClinVar, literature, or other databases — have reported this variant in any affected individual. Details ▾Hide ▴
Evidence considered
- No independent sources reporting this variant in affected individuals
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_001184.3:c.2804A>C is a missense substitution (p.Gln935Pro) and does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense substitution at position 2804
- protein change p.Gln935Pro
- variant_bucket=other
- apply_generic_pvs1_framework=false
Sources
pvs1_variant_assessmentpvs1_generic_framework ↗
PM5 N/ANo same-residue comparator variants identified. PM5 candidate harvesting was unable to confirm classic same-residue PM5 semantics; no ClinVar entries exist at position Gln935 for ATR. Details ▾Hide ▴
Evidence considered
- Zero same-residue candidates found
- PM5 not applicable
Sources
pm5_candidates
BP7 N/ANM_001184.3:c.2804A>C is a missense substitution resulting in p.Gln935Pro. BP7 applies only to synonymous variants with no predicted splice impact and is not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is reserved for synonymous/intronic variants
Identifiers
- Gene
- ATR
- Transcript
- NM_001184.3
- Coding (HGVS c.)
- NM_001184.3:c.2804A>C
- Protein (HGVS p.)
- NP_001175.2:p.(Gln935Pro)
- GRCh38
- chr3:142553228 T>G
- GRCh37
- chr3:142272070 T>G
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
- 0.520
- BayesDel
- 0.216
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no deleterious impact. SpliceAI predicts no significant splicing effect (max delta score 0.17, below 0.2 threshold). BayesDel score is 0.216, below the typical deleterious threshold. REVEL score is 0.52 (indeterminate, does not support a pathogenic classification). The aggregate in silico evidence does not support a damaging effect on the gene product. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta 0.17 (no splicing impact)
- BayesDel 0.216 (low/benign range)
- REVEL 0.52 (indeterminate)
Sources
PP3 Multiple lines of computational evidence do not support a deleterious effect. REVEL score is 0.52 (indeterminate, below typical pathogenic threshold of 0.75). BayesDel score is 0.216 (below typical deleterious threshold). SpliceAI max delta is 0.17 (no predicted splicing impact, below 0.2 threshold). Taken together, these in silico predictors do not meet the threshold for PP3. Details ▾Hide ▴
Evidence considered
- REVEL 0.52 (indeterminate)
- BayesDel 0.216 (low)
- SpliceAI max delta 0.17 (no splicing impact)
Sources
BP7 N/ANM_001184.3:c.2804A>C is a missense substitution resulting in p.Gln935Pro. BP7 applies only to synonymous variants with no predicted splice impact and is not applicable to missense variants. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is reserved for synonymous/intronic variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.17). REVEL score = 0.52. BayesDel score = 0.216019.
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 0.170
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.2804A%3EC
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-142272070-T-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-142553228-T-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-142553228-T-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001184.3%3Ac.2804…
- OncoKB ↗www.oncokb.org/gene/ATR/Q935P
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATR+c.2804A%3EC
- 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 no significant splice impact for this variant (max delta score = 0.17). REVEL score = 0.52. BayesDel score = 0.216019.
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.