About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.3118A>G, p.(Met1040Val)
Classification
Benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is benign. Select a step to read what it means.
Benign.A benign classification under the recorded framework.
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: 0
Benign evidence criteria: 4
Pathogenic criteria applied · 0
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 4
BA1Stand alone
BA1 · stand alone
This variant exceeds the ATM BA1 threshold of >0.5% grpmax filtering allele frequency in gnomAD v4.1. The highest observed population frequency is 3.97073% in African/African American individuals, with grpmax FAF 3.85176%.
BS1Strong
BS1 · strong
This variant exceeds the ATM BS1 threshold of >0.05% grpmax filtering allele frequency in gnomAD v4.1. The highest observed population frequency is 3.97073% in African/African American individuals, which is far above this threshold.
BP4Supporting
BP4 · supporting
Computational evidence supports a benign effect. REVEL is 0.096, below the ATM BP4 missense threshold of ≤0.249, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, below the BP4 splice threshold of ≤0.1. BayesDel is also negative at -0.451498, which is concordant with a benign computational profile.
BP6Supporting
BP6 · supporting
Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Benign.
Recorded classification: Benign
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule17 (1 Benign.Stand Alone) with applied criteria: BA1 stand-alone benign, BS1 strong, BP4 supporting, BP6 supporting benign; maps to Benign.
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
3,384 / 1,613,784 alleles
gnomAD v4.1: 3,384 / 1,613,784 alleles. Recorded AF 0.00209693. Recorded homozygote count 67.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00399369; MAF= 0.39937%, 1129/282696 alleles, homozygotes = 26) and has highest observed frequency in the African/African American population (AF= 0.0418838; MAF= 4.18838%, 1045/24950 alleles, homozygotes = 26); grpmax FAF= 0.0399312.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
28 reported laboratory submissions
22 Benign · 5 Likely benign · 1 benign.
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
4 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV53737085, n = 4 times).
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: 4 met · 3 not met · 6 not assessed · 15 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.3118A>G (p.Met1040Val) variant has been observed in somatic cancers 4 times in COSMIC and is reported in ClinVar as Benign with expert panel review.
This variant is common in population databases, with gnomAD v4.1 showing an overall allele frequency of 0.20969% and an African/African American allele frequency of 3.97073%, which exceeds the ATM BA1 threshold of 0.5% grpmax filtering allele frequency.
Computational evidence supports a benign effect, with REVEL 0.096, BayesDel -0.451498, and SpliceAI maximum delta score 0.01, meeting the ATM BP4 thresholds and not meeting PP3 thresholds.
No criteria match.
Met · 4
BA1 Stand aloneThis variant exceeds the ATM BA1 threshold of >0.5% grpmax filtering allele frequency in gnomAD v4.1. The highest observed population frequency is 3.97073% in African/African American individuals, with grpmax FAF 3.85176%. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.5% in gnomAD v4 dataset
Evidence considered
- ATM BA1 threshold: grpmax filtering AF >0.5% in gnomAD v4
- gnomAD v4.1 African/African American AF 0.0397073
- grpmax FAF 0.0385176
- gnomAD v2.1 African/African American AF 0.0418838
- grpmax FAF 0.0399312
Sources
BS1 StrongThis variant exceeds the ATM BS1 threshold of >0.05% grpmax filtering allele frequency in gnomAD v4.1. The highest observed population frequency is 3.97073% in African/African American individuals, which is far above this threshold. Details ▾Hide ▴
Rule
Grpmax Filtering AF >.05% in gnomAD v4 dataset
Evidence considered
- ATM BS1 threshold: grpmax filtering AF >0.05% in gnomAD v4
- gnomAD v4.1 African/African American AF 0.0397073
- gnomAD v2.1 African/African American AF 0.0418838
Sources
BP4 SupportingComputational evidence supports a benign effect. REVEL is 0.096, below the ATM BP4 missense threshold of ≤0.249, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, below the BP4 splice threshold of ≤0.1. BayesDel is also negative at -0.451498, which is concordant with a benign computational profile. Details ▾Hide ▴
Rule
Missense: REVEL ≤0.249; Splicing: SpliceAI ≤0.1.
Evidence considered
- REVEL 0.096
- SpliceAI max delta score 0.01
- BayesDel -0.451498
Sources
Not met · 3 · evaluated, threshold not reached
PS4 This variant has been reported in ClinVar and 4 times in COSMIC, but no case-control study showing p-value ≤0.05 with odds ratio, hazard ratio, or relative risk ≥2 was identified. Its population frequency in gnomAD v4.1 is 0.20969% overall and 3.97073% in the African/African American population, which does not support enrichment in affected individuals. Details ▾Hide ▴
Rule
Case-control studies; p-value ≤.05 AND (OR/HR/RR ≥2 or lower 95% CI ≥1.5).
Evidence considered
- ClinVar expert panel benign assertion present
- COSMIC somatic count 4
- gnomAD v4.1 total AF 0.00209693
- African/African American AF 0.0397073
Still missing
- A qualifying case-control analysis would be needed for PS4.
Sources
PM2 Population frequency is above the ATM PM2_Supporting threshold of ≤0.001% in gnomAD v4.1. The observed overall AF is 0.20969% and the highest population AF is 3.97073% in African/African American individuals. Details ▾Hide ▴
Rule
Frequency ≤.001% in gnomAD v4 dataset.
Evidence considered
- ATM PM2_Supporting threshold ≤0.001%
- gnomAD v4.1 total AF 0.00209693
- African/African American AF 0.0397073
- gnomAD v2.1 total AF 0.00399369
- African/African American AF 0.0418838
Sources
PP3 Computational evidence does not meet the ATM PP3 threshold. REVEL is 0.096, which is below the missense PP3 cutoff of >0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, below the splice PP3 cutoff of ≥0.2. Details ▾Hide ▴
Rule
Missense: REVEL >.7333; Splicing: SpliceAI ≥0.2.
Evidence considered
- REVEL 0.096
- SpliceAI max delta score 0.01
- BayesDel -0.451498 is also not suggestive of a deleterious effect
Sources
Not assessed · 6 · no assessment recorded
PS1 No established pathogenic or likely pathogenic comparator producing the same amino acid change or the same predicted splice event was identified, so PS1 was not assessed. Details ▾Hide ▴
Rule
Use for missense changes as long as splicing is ruled-out for both alterations.
Evidence considered
- Missense PS1 requires an eligible pathogenic/likely pathogenic comparator and splicing ruled out
- SpliceAI max delta score 0.01
Still missing
- A validated same-amino-acid or same-splicing-event pathogenic comparator would be needed.
Sources
PS3 No validated ATM functional study for this exact variant was identified showing failure to rescue an ATM-specific feature or radiosensitivity in a manner that meets the ATM PS3 framework. Details ▾Hide ▴
Rule
Use when a variant fails to rescue an ATM specific feature and/or radiosensitivity per ATM VCEP framework.
Evidence considered
- ATM PS3 requires failure to rescue ATM-specific functional readouts and/or radiosensitivity
- No exact c.3118A>G or p.Met1040Val entry was identified in the reviewed ATM functional assay tables
Still missing
- An accepted variant-specific ATM functional assay result would be needed.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
PM3 No confirmed observation of this variant in trans with a pathogenic or likely pathogenic ATM variant in an individual with ataxia-telangiectasia was identified. Details ▾Hide ▴
Rule
PM3 point-based ATM framework for recessive disease.
Evidence considered
- ATM PM3/BP2 point-based framework reviewed
- No qualifying trans observation identified
Still missing
- Phase-confirmed biallelic ATM case data would be needed.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
PP1 No segregation data were identified for this variant, so PP1 was not assessed. Details ▾Hide ▴
Rule
AR condition: segregation in affected relatives.
Evidence considered
- ATM PP1 requires segregation in affected relatives
Still missing
- Family segregation data would be needed.
Sources
BS3 No validated ATM functional study for this exact variant was identified showing rescue of an ATM-specific feature and/or radiosensitivity in a manner that meets the ATM BS3 framework. Details ▾Hide ▴
Rule
Use when a variant rescues ATM-specific feature(s) and/or radiosensitivity per ATM VCEP framework.
Evidence considered
- ATM BS3 requires normal function in approved ATM assays
- No exact c.3118A>G or p.Met1040Val entry was identified in the reviewed ATM functional assay tables
Still missing
- An accepted variant-specific ATM functional assay result would be needed.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BP2 No confirmed cis or trans co-occurrence data with a pathogenic or likely pathogenic ATM variant in an unaffected non-ataxia-telangiectasia individual were identified, so BP2 was not assessed. Details ▾Hide ▴
Rule
BP2 point-based ATM framework for unaffected non-A-T individuals.
Evidence considered
- ATM PM3/BP2 point-based framework reviewed
- No qualifying benign co-occurrence observation identified
Still missing
- Qualifying co-occurrence data with phase and phenotype information would be needed.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AThis is a missense variant, and available evidence does not indicate a null effect or canonical splice-site disruption; therefore the ATM PVS1 rule does not apply. Details ▾Hide ▴
Rule
Use ATM PVS1 Decision Tree
Evidence considered
- ATM CSPEC includes PVS1 guidance
- Generic PVS1 scaffold does not place this variant in a null-variant bucket
- SpliceAI max delta score 0.01 does not support a splice-mediated null effect
Sources
PS2 VCEPThe ATM CSPEC marks PS2 as not applicable in this framework. Details ▾Hide ▴
PM1 VCEPThe ATM CSPEC marks PM1 as not applicable in this framework. Details ▾Hide ▴
PM4 N/AThis is not a stop-loss variant, so PM4 does not apply. Details ▾Hide ▴
Rule
Use for stop-loss variants.
Evidence considered
- ATM PM4 is specified for stop-loss variants
Sources
PM5 N/AIn the ATM CSPEC, PM5 is not classic same-residue missense logic for this variant type. The reviewed PM5 candidate file indicates that PM5 is a truncation-cutoff or non-missense rule here, so it does not apply to this missense change. Details ▾Hide ▴
Rule
Apply to truncating or qualifying splice variants upstream of p.Arg3047.
Evidence considered
- ATM PM5 framework is truncation/splice-specific rather than classic missense PM5 for this case
- PM5 candidate review marked classic PM5 as ineligible
Sources
cspec ↗pm5_candidates
PM6 VCEPThe ATM CSPEC marks PM6 as not applicable in this framework. Details ▾Hide ▴
PP2 VCEPThe ATM CSPEC marks PP2 as not applicable in this framework. Details ▾Hide ▴
PP4 VCEPThe ATM CSPEC marks PP4 as not applicable in this framework. Details ▾Hide ▴
PP5 VCEPThe ATM CSPEC marks PP5 as not applicable in this framework. Details ▾Hide ▴
BS2 VCEPThe ATM CSPEC marks BS2 as not applicable in this framework. Details ▾Hide ▴
BS4 VCEPThe ATM CSPEC marks BS4 as not applicable in this framework. Details ▾Hide ▴
BP1 VCEPThe ATM CSPEC marks BP1 as not applicable in this framework. Details ▾Hide ▴
BP3 VCEPThe ATM CSPEC marks BP3 as not applicable in this framework. Details ▾Hide ▴
BP5 VCEPThe ATM CSPEC marks BP5 as not applicable in this framework. Details ▾Hide ▴
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 does not apply. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-based benign evidence may also apply.
Evidence considered
- ATM BP7 is specified for synonymous and deep intronic variants
- SpliceAI max delta score 0.01
Sources
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.3
- Coding (HGVS c.)
- NM_000051.3:c.3118A>G
- Protein (HGVS p.)
- NP_000042.3:p.(Met1040Val)
- GRCh38
- chr11:108272572 A>G
- GRCh37
- chr11:108143299 A>G
- ClinVar
- 3027
- COSMIC
- COSV53737085
Gene diagram
Every interpreted variant in ATM, mapped onto the exon structure of NM_000051.3. Select a row to find it on the plot.
ATMNM_000051.3
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 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
3,384 / 1,613,784 alleles
AF 0.0021 · 67 homozygotes · FAF 0.0385
gnomAD v2.1
1,129 / 282,696 alleles
AF 0.00399 · 26 homozygotes · FAF 0.0399
By genetic ancestry
gnomAD v4.1
AF 0.0021 · 3384 / 1,613,784 alleles · 67 hom · FAF 0.039
| African/African American2979 / 75,024 | 0.0467 hom |
| Remaining individuals190 / 62,490 | 0.003 |
| Admixed American162 / 60,024 | 0.0027 |
| Middle Eastern9 / 6,056 | 0.0015 |
| South Asian15 / 91,076 | 0.00016 |
| European (non-Finnish)29 / 1,179,760 | 2.5e-05 |
0 alternate alleles recorded in 4 other groups: European (Finnish), Amish, East Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.004 · 1129 / 282,696 alleles · 26 hom · FAF 0.04
| African/African American1045 / 24,950 | 0.04226 hom |
| Admixed American62 / 35,420 | 0.0018 |
| Remaining individuals11 / 7,212 | 0.0015 |
| South Asian3 / 30,608 | 9.8e-05 |
| European (non-Finnish)8 / 129,074 | 6.2e-05 |
0 alternate alleles recorded in 3 other groups: Ashkenazi Jewish, East Asian, European (Finnish).
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.00209693; MAF= 0.20969%, 3384/1613784 alleles, homozygotes = 67) and has highest observed frequency in the African/African American population (AF= 0.0397073; MAF= 3.97073%, 2979/75024 alleles, homozygotes = 67); grpmax FAF= 0.0385176.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00399369; MAF= 0.39937%, 1129/282696 alleles, homozygotes = 26) and has highest observed frequency in the African/African American population (AF= 0.0418838; MAF= 4.18838%, 1045/24950 alleles, homozygotes = 26); grpmax FAF= 0.0399312.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.096
- BayesDel
- -0.451
How the predictions were used
BP4 SupportingComputational evidence supports a benign effect. REVEL is 0.096, below the ATM BP4 missense threshold of ≤0.249, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, below the BP4 splice threshold of ≤0.1. BayesDel is also negative at -0.451498, which is concordant with a benign computational profile. Details ▾Hide ▴
Rule
Missense: REVEL ≤0.249; Splicing: SpliceAI ≤0.1.
Evidence considered
- REVEL 0.096
- SpliceAI max delta score 0.01
- BayesDel -0.451498
Sources
PP3 Computational evidence does not meet the ATM PP3 threshold. REVEL is 0.096, which is below the missense PP3 cutoff of >0.7333, and SpliceAI predicts no significant splice impact with a maximum delta score of 0.01, below the splice PP3 cutoff of ≥0.2. Details ▾Hide ▴
Rule
Missense: REVEL >.7333; Splicing: SpliceAI ≥0.2.
Evidence considered
- REVEL 0.096
- SpliceAI max delta score 0.01
- BayesDel -0.451498 is also not suggestive of a deleterious effect
Sources
BP7 N/AThis is a missense variant rather than a synonymous or deep intronic change, so BP7 does not apply. Details ▾Hide ▴
Rule
Use for synonymous and deep intronic variants; RNA-based benign evidence may also apply.
Evidence considered
- ATM BP7 is specified for synonymous and deep intronic variants
- SpliceAI max delta score 0.01
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.096. BayesDel score = -0.451498.
9 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
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PMID 11443540 ↗Global analysis of ATM polymorphism reveals significant functional constraint.Thorstenson YR et al. · 2001No paper-specific finding is recorded.
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PMID 17640065 ↗A systematic evaluation of the ataxia telangiectasia mutated gene does not show an association with non-Hodgkin lymphoma.Sipahimalani P et al. · 2007No paper-specific finding is recorded.
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PMID 20305132 ↗Radiation exposure, the ATM Gene, and contralateral breast cancer in the women's environmental cancer and radiation epidemiology study.Bernstein JL et al. · 2010No paper-specific finding is recorded.
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PMID 22529920 ↗Computational refinement of functional single nucleotide polymorphisms associated with ATM gene.George Priya Doss C et al. · 2012No paper-specific finding is recorded.
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PMID 25625042 ↗ATM gene mutations in sporadic breast cancer patients from Brazil.Mangone FR et al. · 2015No paper-specific finding is recorded.
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PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.No paper-specific finding is recorded.
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PMID 26467025 ↗A Standardized DNA Variant Scoring System for Pathogenicity Assessments in Mendelian Disorders.No paper-specific finding is recorded.
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PMID 9288106 ↗Clustering of missense mutations in the ataxia-telangiectasia gene in a sporadic T-cell leukaemia.No paper-specific finding is recorded.
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.No paper-specific finding is recorded.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
3,384 / 1,613,784 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
22 Benign · 5 Likely benign · 1 benign
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/3027/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108143299-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108272572-A-G?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.3%3Ac.3118…
- OncoKB ↗www.oncokb.org/gene/ATM/M1040V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=105142862
- 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= 0.00209693; MAF= 0.20969%, 3384/1613784 alleles, homozygotes = 67) and has highest observed frequency in the African/African American population (AF= 0.0397073; MAF= 3.97073%, 2979/75024 alleles, homozygotes = 67); grpmax FAF= 0.0385176.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.00399369; MAF= 0.39937%, 1129/282696 alleles, homozygotes = 26) and has highest observed frequency in the African/African American population (AF= 0.0418838; MAF= 4.18838%, 1045/24950 alleles, homozygotes = 26); grpmax FAF= 0.0399312.
ClinVar
This variant has been reported in ClinVar as Benign (22 clinical laboratories) and as Likely benign (5 clinical laboratories) and as benign (1 clinical laboratory) and as Benign by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 3027)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.096. BayesDel score = -0.451498.
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; COSV53737085, n = 4 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.