About ATR
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATR c.6680A>G, p.(Asn2227Ser)
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: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
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 moderate; combination = 1 moderate, 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
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
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.
29 criteria with recorded statuses: 1 met · 21 not met · 1 not assessed · 6 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.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).
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).
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.
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).
No criteria match.
Met · 1
PM2 ModerateThe 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. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: absent (AC=null
- AN=null
- AF=null)
- gnomAD v4.1: absent (AC=null
- gnomAD-Canada v1.0: absent (AC=0
- AN=0
- AF=0.0)
Sources
Not met · 21 · evaluated, threshold not reached
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. No same-residue comparators were found in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No pathogenic or likely pathogenic variant at the same amino acid residue (N2227) identified in ClinVar or candidate search.
Still missing
- Comprehensive ClinVar search for alternate nucleotide changes at c.6680 producing p.Asn2227Ser.
Sources
clinvar ↗pm5_candidates
PS2 No data on de novo occurrence of this variant were identified. No parental testing results or family studies are available in the case materials. Details ▾Hide ▴
Still missing
- Parental testing data not available
- no trio sequencing or de novo analysis performed.
PS3 No functional data were identified for NM_001184.3:c.6680A>G (p.Asn2227Ser) in OncoKB, the literature, or other curated sources. OncoKB classifies this variant as Unknown Oncogenic Effect. No publications with variant-specific functional assays were found. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional data. No publications with functional assays for this variant identified.
Still missing
- No functional studies (enzymatic
- splicing
- protein interaction) have been performed on this variant.
Sources
PS4 No case-control studies or prevalence data comparing this variant in affected vs. unaffected individuals are available. The variant has been reported only once in ClinVar as a VUS with a single clinical laboratory submission. Details ▾Hide ▴
Evidence considered
- ClinVar: 1 submitter
- classification=Uncertain significance. No case-control or cohort data.
Still missing
- No case-control data
- variant not observed in any published disease cohort with statistical comparison to controls.
Sources
PM1 The variant (p.Asn2227Ser) is not located in a statistically significant mutational hotspot per cancerhotspots.org. No well-characterized critical functional domain encompassing residue 2227 has been defined in the case materials, and no VCEP/CSPEC domain specification exists for ATR. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: residue not significant. No VCEP domain definition for ATR.
Still missing
- Domain-level characterization of ATR C-terminal region (residue 2227) not available in case materials.
PM5 No pathogenic or likely pathogenic missense variants at the same amino acid residue (p.Asn2227) were identified in ClinVar or the candidate search. The automatic PM5 candidate harvest returned zero same-residue candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: 0 same-residue candidates
- eligible_for_classic_pm5_search=false. No expert panel P/LP variants at N2227.
Still missing
- ClinVar may contain same-residue variants not captured by the automated search
- manual review of ClinVar for all N2227 substitutions recommended.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation (confirmed or unconfirmed) of this variant was identified. No family studies with parental testing are available. Details ▾Hide ▴
Still missing
- No trio sequencing or de novo analysis available.
PP1 No co-segregation data are available for this variant. No family studies or pedigree analysis was identified in the case materials. Details ▾Hide ▴
Still missing
- No family segregation data available
- co-segregation analysis not possible.
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.545 (borderline, below the typical 0.75 pathogenic threshold), BayesDel score is -0.21413 (benign range), and SpliceAI predicts no splicing impact (max delta score = 0.00). The computational evidence is equivocal to benign and does not meet PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.545 (borderline
- below pathogenic threshold of 0.75)
- BayesDel: -0.21413 (benign range
- score < 0)
- SpliceAI: max delta 0.00 (no predicted splice impact)
Sources
PP4 No phenotypic data for the proband or affected individuals carrying this variant are available in the case materials. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology, which cannot be evaluated without clinical information. Details ▾Hide ▴
Still missing
- No proband phenotype data provided
- cannot assess clinical specificity.
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★). PP5 requires a reputable source (≥3★ expert panel) to have classified the variant as pathogenic; 1★ VUS does not meet this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- 1★ (criteria provided
- single submitter)
- 1 clinical laboratory. No expert panel classification.
Sources
BA1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, which is far below the BA1 threshold of >1% in any population. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% across all gnomAD datasets
- does not exceed 1% BA1 threshold.
Sources
BS1 The variant is absent from gnomAD v2.1, v4.1, and gnomAD-Canada. The allele frequency is 0%, which is below the BS1 threshold of >0.3% in any population. Details ▾Hide ▴
Evidence considered
- Allele frequency 0% across all gnomAD datasets
- does not exceed 0.3% BS1 threshold.
Sources
BS2 No observation of this variant in a homozygous or hemizygous state in healthy adults was identified. gnomAD reports no homozygous individuals for this variant. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 and v4.1: no homozygous individuals observed.
Sources
BS3 No well-established functional studies showing no damaging effect of this variant were identified. OncoKB reports Unknown Oncogenic Effect, and no publications with variant-specific functional assays demonstrating benign effect are available. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect. No functional studies demonstrating benign effect.
Still missing
- No functional studies (enzymatic
- protein interaction
- splicing) have been performed on this variant.
Sources
BS4 No family segregation data are available to demonstrate lack of co-segregation with disease. No pedigree analysis or affected family member testing data were provided. Details ▾Hide ▴
Still missing
- No family data
- cannot assess non-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. BP1 requires demonstration that the gene primarily causes disease through truncating variants and that missense variants are a rare or unknown mechanism, which has not been established for ATR. Details ▾Hide ▴
Evidence considered
- ATR LOF mechanism supported
- but no evidence that missense variants are not also pathogenic. Gene-level constraint for missense not characterized in case materials.
Still missing
- Gene-level missense constraint data (Z-score
- o/e ratio) not evaluated
- ATR may have missense-mediated disease mechanisms.
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a known pathogenic variant in a fully penetrant dominant disorder. ATR-associated germline disease inheritance pattern is not well-defined, and no phasing data are available. Details ▾Hide ▴
Still missing
- No phasing or trans-configuration data available.
BP4 In silico evidence is mixed and does not provide multiple consistent lines supporting no impact. REVEL score is 0.545 (borderline, neither clearly benign nor pathogenic), BayesDel is -0.21413 (benign range), and SpliceAI predicts no splicing impact (max delta 0.00). While BayesDel suggests a benign effect, REVEL is equivocal rather than clearly benign. The evidence is not sufficiently consistent across multiple predictors to meet BP4. Details ▾Hide ▴
Evidence considered
- REVEL: 0.545 (borderline
- neither clearly pathogenic nor benign)
- BayesDel: -0.21413 (benign range)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
BP5 No alternate molecular cause for the observed phenotype was identified in the case materials. No evidence of a different pathogenic variant explaining the phenotype is available. Details ▾Hide ▴
Still missing
- No phenotype or alternate genetic findings provided.
BP6 This variant is classified as Uncertain significance in ClinVar (ClinVarID 2624947) by a single clinical laboratory (1★). BP6 requires a reputable source (≥3★ expert panel) to have classified the variant as benign or likely benign; 1★ VUS does not meet this threshold. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- 1★ (criteria provided
- single submitter)
- 1 clinical laboratory. No benign classification by expert panel.
Sources
Not assessed · 1 · no assessment recorded
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. PP2 requires evidence that the gene has a low rate of benign missense variation and that missense variants are a common disease mechanism. Without this data, PP2 cannot be reliably assessed under generic ACMG. Details ▾Hide ▴
Evidence considered
- HCI prior: not found. No gene-level missense constraint data available in case materials.
Still missing
- HCI prior probability unavailable
- no gnomAD missense Z-score or o/e constraint metric for ATR in this dataset.
Not applicable · 6· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant (NP_001175.2:p.Asn2227Ser); it does not fall into the default 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 variant not eligible for PVS1 under generic framework
- variant_bucket=other
- apply_generic_pvs1_framework=false.
Sources
PM3 N/ASkipped per pre-adjudication instruction: recessive disorder trans-configuration criterion not assessed. Details ▾Hide ▴
No further detail was recorded.
PM4 N/ASkipped per pre-adjudication instruction: protein length change criterion not applicable to this substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ASkipped per pre-adjudication instruction: in-frame deletion/insertion criterion not applicable to this substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/AThis is a missense variant (c.6680A>G, p.Asn2227Ser), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- not eligible for BP7.
PS5 N/APS5 is not a standard ACMG/AMP 2015 criterion and no VCEP/CSPEC framework is available for ATR that defines PS5. This case uses generic_acmg framework. Details ▾Hide ▴
Sources
generic_acmg_combination_rules
Identifiers
- Gene
- ATR
- Transcript
- NM_001184.3
- Coding (HGVS c.)
- NM_001184.3:c.6680A>G
- Protein (HGVS p.)
- NP_001175.2:p.(Asn2227Ser)
- GRCh38
- chr3:142467941 T>C
- GRCh37
- chr3:142186783 T>C
- ClinVar
- 2624947
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
- 0.545
- BayesDel
- -0.214
How the predictions were used
PP3 Multiple lines of in silico evidence do not support a deleterious effect. REVEL score is 0.545 (borderline, below the typical 0.75 pathogenic threshold), BayesDel score is -0.21413 (benign range), and SpliceAI predicts no splicing impact (max delta score = 0.00). The computational evidence is equivocal to benign and does not meet PP3. Details ▾Hide ▴
Evidence considered
- REVEL: 0.545 (borderline
- below pathogenic threshold of 0.75)
- BayesDel: -0.21413 (benign range
- score < 0)
- SpliceAI: max delta 0.00 (no predicted splice impact)
Sources
BP4 In silico evidence is mixed and does not provide multiple consistent lines supporting no impact. REVEL score is 0.545 (borderline, neither clearly benign nor pathogenic), BayesDel is -0.21413 (benign range), and SpliceAI predicts no splicing impact (max delta 0.00). While BayesDel suggests a benign effect, REVEL is equivocal rather than clearly benign. The evidence is not sufficiently consistent across multiple predictors to meet BP4. Details ▾Hide ▴
Evidence considered
- REVEL: 0.545 (borderline
- neither clearly pathogenic nor benign)
- BayesDel: -0.21413 (benign range)
- SpliceAI: max delta 0.00 (no splicing impact)
Sources
BP7 N/AThis is a missense variant (c.6680A>G, p.Asn2227Ser), not a synonymous or intronic variant. BP7 applies only to synonymous variants with no predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense variant
- not eligible for BP7.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.545. BayesDel score = -0.21413.
5 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 23619275 ↗ACMG position statement on prenatal/preconception expanded carrier screening.ACMG position statement on prenatal/preconception expanded carrier screening. Discusses criteria for selecting disorders for population carrier screening panels. ATR and NM_001184.3:c.6680A>G are not mentioned.Does not name this variant
-
PMID 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.Edwards JG et al. · 2015Joint statement on expanded carrier screening in reproductive medicine from ACMG, ACOG, NSGC, Perinatal Quality Foundation, and SMFM. Provides guidance on offering expanded carrier screening panels. ATR and NM_001184.3:c.6680A>G are not mentioned.Does not name this variant
-
PMID 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.Therrell BL et al. · 2013Recommendations on including newborn screening bloodspot collection device serial numbers on birth certificates. Discusses newborn screening program logistics. ATR and NM_001184.3:c.6680A>G are not mentioned.Does not name this variant
-
PMID 24022298 ↗Offering prenatal diagnostic tests: European guidelines for clinical practice [corrected].Skirton H et al. · 2014European guidelines for offering prenatal diagnostic tests in clinical practice. Discusses ethical and practical aspects of prenatal testing. ATR and NM_001184.3:c.6680A>G are not mentioned.Does not name this variant
-
PMID 24394680 ↗Parental permission for pilot newborn screening research: guidelines from the NBSTRN.Botkin JR et al. · 2014Guidelines from the Newborn Screening Translational Research Network (NBSTRN) on parental permission for pilot newborn screening research. Discusses consent and ethical frameworks. ATR and NM_001184.3:c.6680A>G are not mentioned.Does not name this variant
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 0.000
Open source ↗
ClinVar
1 Uncertain significance
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/variation/2624947/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/3-142186783-T-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr3-142467941-T-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/3-142467941-T-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_001184.3%3Ac.6680…
- OncoKB ↗www.oncokb.org/gene/ATR/N2227S
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATR+c.6680A%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 has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 2624947)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.545. BayesDel score = -0.21413.
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.