About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.4247A>G, p.(Gln1416Arg)
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
PM2Supporting
PM2 · supporting
This variant is extremely rare in population databases. In gnomAD v4.1, the allele frequency is 8.72e-06 (0.00087%; 14/1,604,866 alleles, 0 homozygotes) with grpmax filtering AF of 6.17e-06 (0.000617%). This is well below the ATM VCEP v1.5.0 PM2_Supporting threshold of ≤0.001% in gnomAD v4. The variant is also rare in gnomAD v2.1 (AF=1.63e-05; 4/245,772 alleles).
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: PM2 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
14 / 1,604,866 alleles
gnomAD v4.1: 14 / 1,604,866 alleles. Recorded AF 8.72347e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.62752e-05; MAF= 0.00163%, 4/245772 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.57961e-05; MAF= 0.00358%, 4/111744 alleles, homozygotes = 0); grpmax FAF= 1.136e-05.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
6 reported laboratory submissions
6 Uncertain significance.
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
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 ClinGen ATM VCEP v1.5.0, with the data and sources behind each one.
26 criteria with recorded statuses: 1 met · 5 not met · 5 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
NM_000051.4:c.4247A>G (p.Gln1416Arg) is a rare missense variant in ATM with an allele frequency of 0.00087% in gnomAD v4.1 (14/1,604,866 alleles, 0 homozygotes), meeting PM2_Supporting under the ClinGen HBOP VCEP v1.5.0 threshold of ≤0.001%.
Computational predictors are inconclusive: REVEL score of 0.45 falls between the VCEP thresholds for PP3 (>0.7333) and BP4 (≤0.249), and BayesDel score of -0.0913068 is weakly benign. SpliceAI predicts no splicing impact (max delta=0.04). Neither PP3 nor BP4 is met.
This variant has been reported in ClinVar as Uncertain Significance by 6 clinical laboratories (ClinVar Variation ID: 230064, review status: criteria provided, single submitter). No expert panel classification has been recorded.
No variant-specific functional data (PS3/BS3), case-control studies (PS4), segregation data (PP1), or co-occurrence data (BP2) were identified for this variant. OncoKB reports Unknown Oncogenic Effect. The variant has not been reported in COSMIC.
With only PM2_Supporting met and no pathogenic moderate/strong/very strong criteria fulfilled, this variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP framework as specified by the ClinGen HBOP VCEP for ATM v1.5.0.
No criteria match.
Met · 1
PM2 SupportingThis variant is extremely rare in population databases. In gnomAD v4.1, the allele frequency is 8.72e-06 (0.00087%; 14/1,604,866 alleles, 0 homozygotes) with grpmax filtering AF of 6.17e-06 (0.000617%). This is well below the ATM VCEP v1.5.0 PM2_Supporting threshold of ≤0.001% in gnomAD v4. The variant is also rare in gnomAD v2.1 (AF=1.63e-05; 4/245,772 alleles). Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 AF=0.00087% (≤0.001% VCEP threshold)
- grpmax FAF=0.000617%
- 14/1
- 604
- 866 alleles
- 0 homozygotes.
- gnomAD v2.1 AF=0.00163%
- 4/245
- 772 alleles
Sources
Not met · 5 · evaluated, threshold not reached
PS1 PS1 requires a known (likely) pathogenic missense variant at the same nucleotide position with the same predicted amino acid change and splicing ruled out for both. No such comparator variant was identified at this codon in ClinVar or the available literature. No evidence to support PS1. Details ▾Hide ▴
PP3 Under ATM VCEP v1.5.0, PP3 for missense variants requires a REVEL score >0.7333. The REVEL score for p.Gln1416Arg is 0.45, which falls below this threshold. SpliceAI predicts no significant splicing impact (max delta = 0.04), so the splicing PP3 pathway (SpliceAI ≥0.2) does not apply. The BayesDel score is -0.0913068, which is not strongly damaging. Details ▾Hide ▴
Evidence considered
- REVEL=0.45 (<0.7333 VCEP threshold for PP3).
- SpliceAI max delta=0.04 (<0.2 threshold).
- BayesDel=-0.0913068.
Sources
BA1 Under ATM VCEP v1.5.0, BA1 requires a grpmax filtering AF >0.5% in gnomAD v4. The observed grpmax FAF is 6.17e-06 (0.000617%), far below this threshold. The variant is extremely rare, not common. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF=0.000617% (<0.5% VCEP BA1 threshold).
Sources
BS1 Under ATM VCEP v1.5.0, BS1 requires a grpmax filtering AF >0.05% in gnomAD v4. The observed grpmax FAF is 6.17e-06 (0.000617%), far below this threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1 grpmax FAF=0.000617% (<0.05% VCEP BS1 threshold).
Sources
BP4 Under ATM VCEP v1.5.0, BP4 for missense variants requires a REVEL score ≤0.249. The REVEL score for p.Gln1416Arg is 0.45, which exceeds this threshold. While SpliceAI predicts no splicing impact (max delta=0.04), the splicing BP4 pathway applies specifically to splicing variants, not this missense. The BayesDel score of -0.0913068 is weakly in the benign direction but does not override the VCEP-specific REVEL threshold. Details ▾Hide ▴
Evidence considered
- REVEL=0.45 (>0.249 VCEP BP4 missense threshold).
- SpliceAI max delta=0.04.
- BayesDel=-0.0913068.
Sources
Not assessed · 5 · no assessment recorded
PS3 No variant-specific functional assay data were identified for NM_000051.4:c.4247A>G (p.Gln1416Arg). OncoKB reports Unknown Oncogenic Effect; no publications with direct functional characterization of this variant were found. Under ATM VCEP v1.5.0, PS3 requires demonstration that the variant fails to rescue ATM-specific features (e.g., phosphorylation of ATM targets) and/or radiosensitivity. Details ▾Hide ▴
PS4 No variant-specific case-control study with adequate statistical power was identified for NM_000051.4:c.4247A>G. The large-scale ATM studies identified (e.g., PMID:33471991, Dorling et al. 2021) focused on protein-truncating variants and did not provide variant-level data for this missense change. Under ATM VCEP v1.5.0, PS4 requires case-control studies with p-value ≤0.05 and OR ≥2 or lower 95% CI ≥1.5. Details ▾Hide ▴
Evidence considered
- No variant-specific case-control data meeting VCEP thresholds.
Still missing
- No variant-specific case-control study for c.4247A>G.
Sources
cspec ↗33471991
PP1 No segregation data were identified for NM_000051.4:c.4247A>G. Under ATM VCEP v1.5.0, PP1 is applied under an autosomal recessive model (Ataxia Telangiectasia) with segregation in affected relatives. No family studies with this variant were found. Details ▾Hide ▴
Evidence considered
- No segregation data available for this variant.
Still missing
- No family segregation studies identified.
Sources
BS3 No variant-specific functional rescue data were identified for NM_000051.4:c.4247A>G (p.Gln1416Arg). Under ATM VCEP v1.5.0, BS3 requires demonstration that the variant rescues ATM-specific features and/or radiosensitivity. No such studies were found. Details ▾Hide ▴
Evidence considered
- No functional rescue data for this variant.
Still missing
- No functional rescue assay data for p.Gln1416Arg.
Sources
BP2 No co-occurrence (in trans with a pathogenic ATM variant) data were identified for NM_000051.4:c.4247A>G. Under ATM VCEP v1.5.0, BP2 assigns negative points per proband when the variant co-occurs in trans with a known pathogenic variant in an Ataxia Telangiectasia proband. No such observations were found in the available evidence. Details ▾Hide ▴
Evidence considered
- No co-occurrence data with a known pathogenic ATM variant in trans.
Still missing
- No co-occurrence/phase data in A-T probands.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable: NM_000051.4:c.4247A>G is a missense variant (p.Gln1416Arg), which does not fall into the null-variant categories (nonsense, frameshift, canonical +/-1,2 splice sites) required for PVS1 under the ATM VCEP v1.5.0 decision tree. Details ▾Hide ▴
Evidence considered
- Variant is missense p.Gln1416Arg
- not a null variant type eligible for PVS1.
Sources
PS2 VCEPPS2 is listed as Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
PM1 VCEPPM1 is listed as Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
PM5 N/AUnder ATM VCEP v1.5.0, PM5 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with PVS1_VS(RNA) applied. NM_000051.4:c.4247A>G is a missense variant (p.Gln1416Arg) and does not meet these criteria. No same-residue missense comparators were identified via the PM5 candidate search. Details ▾Hide ▴
Evidence considered
- Variant is missense
- VCEP PM5 reserved for truncating/frameshift variants upstream of p.Arg3047.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
PM6 VCEPPM6 is listed as Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
PP2 VCEPPP2 is listed as Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
PP4 VCEPPP4 is listed as Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
PP5 VCEPPP5 is listed as Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
BS2 VCEPBS2 is listed as Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
BS4 VCEPBS4 is listed as Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
BP1 VCEPBP1 is listed as Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
BP5 VCEPBP5 is listed as Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
BP6 VCEPBP6 is listed as Not Applicable by the ATM VCEP v1.5.0. Details ▾Hide ▴
BP7 N/AUnder ATM VCEP v1.5.0, BP7 applies only to synonymous (silent) substitutions and deep intronic variants. NM_000051.4:c.4247A>G is a missense variant (p.Gln1416Arg) and does not qualify. Details ▾Hide ▴
Evidence considered
- Variant is missense
- BP7 reserved for synonymous and deep intronic variants.
Sources
PS5 N/APS5 is not defined in the ATM VCEP v1.5.0 criteria set and is not applicable under this framework. Details ▾Hide ▴
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.4247A>G
- Protein (HGVS p.)
- NP_000042.3:p.(Gln1416Arg)
- GRCh38
- chr11:108289612 A>G
- GRCh37
- chr11:108160339 A>G
- ClinVar
- 230064
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
14 / 1,604,866 alleles
AF 8.72e-06 · 0 homozygotes · FAF 6.17e-06
gnomAD v2.1
4 / 245,772 alleles
AF 1.63e-05 · 0 homozygotes · FAF 1.14e-05
gnomAD-Canada v1.0
0 / 0 alleles
AF 0 · 0 homozygotes · FAF 0
By genetic ancestry
gnomAD v4.1
AF 8.7e-06 · 14 / 1,604,866 alleles · 0 hom · FAF 6.2e-06
| Remaining individuals1 / 62,000 | 1.6e-05 |
| European (non-Finnish)13 / 1,175,936 | 1.1e-05 |
0 alternate alleles recorded in 8 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
gnomAD v2.1
AF 1.6e-05 · 4 / 245,772 alleles · 0 hom · FAF 1.1e-05
| European (non-Finnish)4 / 111,744 | 3.6e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF 0 · 0 / 0 alleles · 0 hom
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 8.72347e-06; MAF= 0.00087%, 14/1604866 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6129e-05; MAF= 0.00161%, 1/62000 alleles, homozygotes = 0); grpmax FAF= 6.17e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.62752e-05; MAF= 0.00163%, 4/245772 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.57961e-05; MAF= 0.00358%, 4/111744 alleles, homozygotes = 0); grpmax FAF= 1.136e-05.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.450
- BayesDel
- -0.091
How the predictions were used
PP3 Under ATM VCEP v1.5.0, PP3 for missense variants requires a REVEL score >0.7333. The REVEL score for p.Gln1416Arg is 0.45, which falls below this threshold. SpliceAI predicts no significant splicing impact (max delta = 0.04), so the splicing PP3 pathway (SpliceAI ≥0.2) does not apply. The BayesDel score is -0.0913068, which is not strongly damaging. Details ▾Hide ▴
Evidence considered
- REVEL=0.45 (<0.7333 VCEP threshold for PP3).
- SpliceAI max delta=0.04 (<0.2 threshold).
- BayesDel=-0.0913068.
Sources
BP4 Under ATM VCEP v1.5.0, BP4 for missense variants requires a REVEL score ≤0.249. The REVEL score for p.Gln1416Arg is 0.45, which exceeds this threshold. While SpliceAI predicts no splicing impact (max delta=0.04), the splicing BP4 pathway applies specifically to splicing variants, not this missense. The BayesDel score of -0.0913068 is weakly in the benign direction but does not override the VCEP-specific REVEL threshold. Details ▾Hide ▴
Evidence considered
- REVEL=0.45 (>0.249 VCEP BP4 missense threshold).
- SpliceAI max delta=0.04.
- BayesDel=-0.0913068.
Sources
BP7 N/AUnder ATM VCEP v1.5.0, BP7 applies only to synonymous (silent) substitutions and deep intronic variants. NM_000051.4:c.4247A>G is a missense variant (p.Gln1416Arg) and does not qualify. Details ▾Hide ▴
Evidence considered
- Variant is missense
- BP7 reserved for synonymous and deep intronic variants.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.45. BayesDel score = -0.0913068.
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 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 28779002 ↗Rare, protein-truncating variants in ATM, CHEK2 and PALB2, but not XRCC2, are associated with increased breast cancer risks.Decker B et al. · 2017No paper-specific finding is recorded.
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PMID 34242744 ↗Customizing local and systemic therapies for women with early breast cancer: the St. Gallen International Consensus Guidelines for treatment of early breast cancer 2021.No paper-specific finding is recorded.
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PMID 15604628 ↗Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.Trepanier A et al. · 2004No paper-specific finding is recorded.
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PMID 17508274 ↗Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.Berliner JL et al. · 2007No paper-specific finding is recorded.
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PMID 18163131 ↗The emerging landscape of breast cancer susceptibility.Stratton MR et al. · 2008No paper-specific finding is recorded.
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PMID 20301425 ↗BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.Adam MP et al. · 1993No paper-specific finding is recorded.
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PMID 20301790 ↗PMID:20301790No 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
14 / 1,604,866 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.040
Open source ↗
ClinVar
6 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 ↗
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/230064/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108160339-A-G?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108289612-A-G?dataset=g…
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.4247…
- OncoKB ↗www.oncokb.org/gene/ATM/Q1416R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.4247A%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
This variant is present in gnomAD v4.1 (AF= 8.72347e-06; MAF= 0.00087%, 14/1604866 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 1.6129e-05; MAF= 0.00161%, 1/62000 alleles, homozygotes = 0); grpmax FAF= 6.17e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 1.62752e-05; MAF= 0.00163%, 4/245772 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.57961e-05; MAF= 0.00358%, 4/111744 alleles, homozygotes = 0); grpmax FAF= 1.136e-05.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (6 clinical laboratories). (ClinVarID = 230064)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.45. BayesDel score = -0.0913068.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.