About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.2222A>G, p.(Tyr741Cys)
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 ClinGen ATM VCEP v1.5.0. 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
PP3Supporting
PP3 · supporting
SpliceAI predicts possible splice impact with a maximum delta score of 0.29, which is above the ATM PP3 splicing threshold of >=0.2 for missense variants. Although REVEL is low at 0.153 and BayesDel is negative at -0.288378, the ATM VCEP rule allows PP3_Supporting for predicted splice impact in missense variants, so PP3_Supporting is met with caution pending RNA confirmation.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework was evaluated deterministically with applied criteria: PP3 supporting; no rule matched the adjudicated criteria.
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
35 / 1,611,122 alleles
gnomAD v4.1: 35 / 1,611,122 alleles. Recorded AF 2.1724e-05. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41539e-05; MAF= 0.00142%, 4/282608 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000100492; MAF= 0.01005%, 2/19902 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
No listed criterion applied
No screenshot for this evidence
Computational predictions
Not recorded
No SpliceAI or REVEL score is recorded in the fields used for this tile.
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. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
Not assessed
No COSMIC evidence statement is recorded in this case.
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under ClinGen ATM VCEP v1.5.0, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 4 not met · 6 not assessed · 17 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
The ATM c.2222A>G (p.Tyr741Cys) variant has been observed once in somatic cancer in COSMIC and has been reported in ClinVar with conflicting germline classifications, including uncertain significance and likely benign submissions.
This variant is present in population databases at low frequency, including gnomAD v4.1 at 0.00217% overall (35/1,611,122 alleles) with a highest observed subpopulation frequency of 0.00447% in East Asian individuals, which is above the ATM PM2_Supporting threshold of <=0.001% and below the BS1 and BA1 thresholds.
Computational evidence is mixed: SpliceAI predicts possible splice impact with a maximum delta score of 0.29, supporting ATM PP3_Supporting, whereas REVEL is low at 0.153 and BayesDel is negative at -0.288378, which argues against a damaging missense effect but does not resolve the predicted splice concern.
No criteria match.
Met · 1
PP3 SupportingSpliceAI predicts possible splice impact with a maximum delta score of 0.29, which is above the ATM PP3 splicing threshold of >=0.2 for missense variants. Although REVEL is low at 0.153 and BayesDel is negative at -0.288378, the ATM VCEP rule allows PP3_Supporting for predicted splice impact in missense variants, so PP3_Supporting is met with caution pending RNA confirmation. Details ▾Hide ▴
Rule
ATM VCEP PP3_Supporting: missense REVEL >0.7333 or predicted splice impact with SpliceAI >=0.2 for missense/in-frame or qualifying noncanonical splice variants.
Evidence considered
- SpliceAI max delta score 0.29.
- REVEL score 0.153.
- BayesDel score -0.288378.
Still missing
- RNA studies were not identified to confirm whether the predicted splice effect occurs in vivo.
Sources
Not met · 4 · evaluated, threshold not reached
PM2 Population frequency does not meet the ATM PM2_Supporting threshold. In gnomAD v4.1 the overall allele frequency is 0.00217% (35/1,611,122) and the highest subpopulation frequency is 0.00447% in East Asian individuals, both above the <=0.001% threshold. Details ▾Hide ▴
Rule
ATM VCEP PM2_Supporting: frequency <=0.001% in gnomAD v4 dataset.
Evidence considered
- gnomAD v4.1 overall AF 2.1724e-05
- East Asian AF 4.47007e-05.
- gnomAD v2.1 also shows the variant at low but non-zero frequency.
Sources
BA1 Population frequency is well below the ATM BA1 threshold. In gnomAD v4.1 the highest observed subpopulation frequency is 0.00447%, which is below the >0.5% threshold. Details ▾Hide ▴
Rule
ATM VCEP BA1: grpmax filtering AF >0.5% in gnomAD v4.
Evidence considered
- gnomAD v4.1 East Asian AF 4.47007e-05.
Sources
BS1 Population frequency is below the ATM BS1 threshold. In gnomAD v4.1 the highest observed subpopulation frequency is 0.00447%, which is below the >0.05% threshold. Details ▾Hide ▴
Rule
ATM VCEP BS1: grpmax filtering AF >0.05% in gnomAD v4.
Evidence considered
- gnomAD v4.1 East Asian AF 4.47007e-05.
Sources
BP4 REVEL is low at 0.153 and BayesDel is negative at -0.288378, which would support a benign missense interpretation, but SpliceAI predicts possible splice impact with a maximum delta score of 0.29, above the ATM no-splice-impact threshold of <=0.1. Because the available computational evidence is conflicting and does not show a clearly benign overall effect, BP4 was not applied. Details ▾Hide ▴
Rule
ATM VCEP BP4: missense REVEL <=0.249 and/or no predicted splice impact with SpliceAI <=0.1; conflicting computational evidence warrants withholding BP4.
Evidence considered
- REVEL score 0.153.
- BayesDel score -0.288378.
- SpliceAI max delta score 0.29.
Still missing
- RNA evidence would help resolve whether the splice prediction is clinically meaningful.
Sources
Not assessed · 6 · no assessment recorded
PS3 No validated ATM functional study was identified showing that this variant fails to rescue an ATM-specific cellular feature or radiosensitivity, so PS3 could not be applied. Details ▾Hide ▴
Rule
ATM VCEP PS3 requires abnormal ATM-specific functional evidence; do not use as strong.
Evidence considered
- OncoKB did not identify variant-specific reviewed functional evidence.
- No ATM rescue or kinase-function assay result was retrieved for this variant.
Still missing
- A variant-specific functional assay with ATM-relevant readouts would be needed.
Sources
PS4 This variant has been reported in ClinVar and once in COSMIC, but no case-control study or robust enrichment data in affected individuals were identified to support PS4. Details ▾Hide ▴
Rule
ATM VCEP PS4 requires case-control evidence with statistical support.
Evidence considered
- ClinVar shows conflicting laboratory classifications.
- COSMIC reports one somatic observation only.
Still missing
- Published case-control or aggregate affected-individual data specific to this variant were not identified.
Sources
PM3 No evidence was identified that this variant was observed in trans with a pathogenic ATM variant in an individual with ataxia-telangiectasia, so PM3 could not be assessed. Details ▾Hide ▴
Rule
ATM VCEP PM3 point-based framework for recessive A-T observations.
Evidence considered
- ATM PM3/BP2 point-based framework was reviewed.
- No qualifying trans observations were retrieved for this variant.
Still missing
- Phase-confirmed recessive case data were not identified.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
PP1 No segregation data were identified for this variant, so PP1 could not be applied. Details ▾Hide ▴
Rule
ATM VCEP PP1 for recessive A-T requires affected relative segregation counts.
Evidence considered
- No published or database-based segregation data were retrieved for this variant.
Still missing
- Family-level segregation evidence was not identified.
Sources
BS3 No validated ATM functional study was identified showing normal or rescued function for this variant, so BS3 could not be applied. Details ▾Hide ▴
Rule
ATM VCEP BS3 requires rescue of ATM-specific function and/or radiosensitivity depending on strength.
Evidence considered
- No variant-specific reviewed functional evidence was retrieved.
- Available scoring resources do not replace a validated functional assay.
Still missing
- A variant-specific assay demonstrating preserved ATM-relevant function would be needed.
Sources
BP2 No evidence was identified that this variant co-occurs in trans with a pathogenic ATM variant in an unaffected individual, so BP2 could not be assessed. Details ▾Hide ▴
Rule
ATM VCEP BP2 point-based framework for benign trans co-occurrence evidence.
Evidence considered
- ATM PM3/BP2 point-based framework was reviewed.
- No qualifying benign co-occurrence observations were retrieved for this variant.
Still missing
- Phase-confirmed co-occurrence data in unaffected individuals were not identified.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 17· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis missense variant does not fall into the ATM PVS1 loss-of-function categories, and no RNA evidence was identified to show a null splicing consequence. Details ▾Hide ▴
Rule
ATM VCEP PVS1 decision framework; generic scaffold does not support default PVS1 application for this missense substitution.
Evidence considered
- ATM VCEP includes PVS1 guidance for loss-of-function variants.
- The variant assessment scaffold places c.2222A>G outside the default null-variant buckets.
Still missing
- RNA studies would be needed to revisit a PVS1(RNA)-type argument.
Sources
PS1 N/APS1 was not applicable because no alternate single-nucleotide ATM variant producing the same Tyr741Cys amino acid change was identified, and the available missense evidence does not establish a same-amino-acid pathogenic reference variant. Details ▾Hide ▴
Rule
ATM VCEP PS1 missense rule requires a same-amino-acid pathogenic comparator with splicing ruled out.
Evidence considered
- ATM-specific PS1 guidance was reviewed.
- No same-amino-acid pathogenic comparator was identified for Tyr741Cys.
Sources
cspec ↗vcep_atm_ps1_1_5
PS2 N/APS2 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks PS2 as not applicable.
Sources
PM1 N/APM1 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks PM1 as not applicable.
Sources
PM4 N/APM4 is not applicable because this variant is a missense substitution, not a stop-loss variant. Details ▾Hide ▴
Rule
ATM VCEP PM4 applicability statement.
Evidence considered
- ATM CSPEC limits PM4 to stop-loss variants.
Sources
PM5 N/APM5 is not applicable because the ATM-specific PM5 rule is limited to truncating or qualifying splice variants upstream of p.Arg3047, and this variant is a missense substitution. Details ▾Hide ▴
Rule
ATM VCEP PM5 applies to specified truncating or splice variants, not missense substitutions like Tyr741Cys.
Evidence considered
- ATM-specific PM5 rule reviewed from CSPEC.
Sources
PM6 N/APM6 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks PM6 as not applicable.
Sources
PP2 N/APP2 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks PP2 as not applicable.
Sources
PP4 N/APP4 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks PP4 as not applicable.
Sources
PP5 N/APP5 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks PP5 as not applicable.
Sources
BS2 N/ABS2 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks BS2 as not applicable.
Sources
BS4 N/ABS4 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks BS4 as not applicable.
Sources
BP1 N/ABP1 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks BP1 as not applicable.
Sources
BP3 N/ABP3 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks BP3 as not applicable.
Sources
BP5 N/ABP5 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks BP5 as not applicable.
Sources
BP6 N/ABP6 is not applicable in the ATM VCEP specifications for this framework. Details ▾Hide ▴
Rule
ATM CSPEC/VCEP applicability statement.
Evidence considered
- ATM CSPEC marks BP6 as not applicable.
Sources
BP7 N/ABP7 is not applicable because this variant is a missense substitution rather than a synonymous or deep intronic variant. Details ▾Hide ▴
Rule
ATM VCEP BP7 applicability statement.
Evidence considered
- ATM CSPEC BP7 rule is limited to synonymous and deep intronic contexts or RNA evidence showing no splice defect.
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.2222A>G
- Protein (HGVS p.)
- NP_000042.3:p.(Tyr741Cys)
- GRCh38
- chr11:108256312 A>G
- GRCh37
- chr11:108127039 A>G
Gene diagram
Every interpreted variant in ATM, mapped onto the exon structure of NM_000051.4. Select a row to find it on the plot.
ATMNM_000051.4
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 ATM
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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
35 / 1,611,122 alleles
AF 2.17e-05 · 0 homozygotes · FAF 1.96e-05
gnomAD v2.1
4 / 282,608 alleles
AF 1.42e-05 · 0 homozygotes · FAF 2.92e-06
By genetic ancestry
gnomAD v4.1
AF 2.2e-05 · 35 / 1,611,122 alleles · 0 hom · FAF 2e-05
| East Asian2 / 44,742 | 4.5e-05 |
| European (non-Finnish)32 / 1,178,146 | 2.7e-05 |
| Remaining individuals1 / 62,304 | 1.6e-05 |
0 alternate alleles recorded in 7 other groups: Admixed American, European (Finnish), Amish, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.4e-05 · 4 / 282,608 alleles · 0 hom · FAF 2.9e-06
| East Asian2 / 19,902 | 0.0001 |
| European (non-Finnish)2 / 129,084 | 1.5e-05 |
0 alternate alleles recorded in 6 other groups: African/African American, Admixed American, Ashkenazi Jewish, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 2.1724e-05; MAF= 0.00217%, 35/1611122 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 4.47007e-05; MAF= 0.00447%, 2/44742 alleles, homozygotes = 0); grpmax FAF= 1.965e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41539e-05; MAF= 0.00142%, 4/282608 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000100492; MAF= 0.01005%, 2/19902 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
PP3 SupportingSpliceAI predicts possible splice impact with a maximum delta score of 0.29, which is above the ATM PP3 splicing threshold of >=0.2 for missense variants. Although REVEL is low at 0.153 and BayesDel is negative at -0.288378, the ATM VCEP rule allows PP3_Supporting for predicted splice impact in missense variants, so PP3_Supporting is met with caution pending RNA confirmation. Details ▾Hide ▴
Rule
ATM VCEP PP3_Supporting: missense REVEL >0.7333 or predicted splice impact with SpliceAI >=0.2 for missense/in-frame or qualifying noncanonical splice variants.
Evidence considered
- SpliceAI max delta score 0.29.
- REVEL score 0.153.
- BayesDel score -0.288378.
Still missing
- RNA studies were not identified to confirm whether the predicted splice effect occurs in vivo.
Sources
BP4 REVEL is low at 0.153 and BayesDel is negative at -0.288378, which would support a benign missense interpretation, but SpliceAI predicts possible splice impact with a maximum delta score of 0.29, above the ATM no-splice-impact threshold of <=0.1. Because the available computational evidence is conflicting and does not show a clearly benign overall effect, BP4 was not applied. Details ▾Hide ▴
Rule
ATM VCEP BP4: missense REVEL <=0.249 and/or no predicted splice impact with SpliceAI <=0.1; conflicting computational evidence warrants withholding BP4.
Evidence considered
- REVEL score 0.153.
- BayesDel score -0.288378.
- SpliceAI max delta score 0.29.
Still missing
- RNA evidence would help resolve whether the splice prediction is clinically meaningful.
Sources
BP7 N/ABP7 is not applicable because this variant is a missense substitution rather than a synonymous or deep intronic variant. Details ▾Hide ▴
Rule
ATM VCEP BP7 applicability statement.
Evidence considered
- ATM CSPEC BP7 rule is limited to synonymous and deep intronic contexts or RNA evidence showing no splice defect.
Sources
Statement
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.29). REVEL score = 0.153. BayesDel score = -0.288378.
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
35 / 1,611,122 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Captured SpliceAI source record
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 ↗
ClinGen CSpec
Captured ClinGen CSpec source record
Open source ↗
All source links
- ClinGen CSpec ↗cspec.genome.network/cspec/ui/svi/doc/639508985
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/236685/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108127039-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108256312-A-G?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.2222…
- OncoKB ↗www.oncokb.org/gene/ATM/Y741C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=105165665
- 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
This variant is present in gnomAD v4.1 (AF= 2.1724e-05; MAF= 0.00217%, 35/1611122 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 4.47007e-05; MAF= 0.00447%, 2/44742 alleles, homozygotes = 0); grpmax FAF= 1.965e-05.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.41539e-05; MAF= 0.00142%, 4/282608 alleles, homozygotes = 0) and has highest observed frequency in the East Asian population (AF= 0.000100492; MAF= 0.01005%, 2/19902 alleles, homozygotes = 0); grpmax FAF= 2.92e-06.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories) and as Likely benign (3 clinical laboratories).
In silico
SpliceAI predicts possible splice impact for this variant (max delta score = 0.29). REVEL score = 0.153. BayesDel score = -0.288378.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. ATM, a kinase involved in the DNA damage response, is mutated in various solid and hematologic malignancies.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV105123853, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.