About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.7835G>A, p.(Arg2612Lys)
Classification
Not classified
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. Select a step to read what it means.
Not classified yet.Select a step to read what it means.
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. 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
This variant is absent from gnomAD v4.1. Under the ATM VCEP PM2 rule, a frequency ≤0.001% in gnomAD v4 qualifies for PM2_Supporting. In gnomAD v2.1, the variant is present at extremely low frequency (AF=3.99×10⁻⁶; 1/250,772 alleles, NFE subpopulation only, no homozygotes).
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
REVEL score is 0.086, which is ≤0.249 (VCEP BP4 threshold for missense variants). SpliceAI predicts no splicing impact (max delta = 0.0, which is ≤0.1). BayesDel score is −0.523 (predicted benign). Multiple independent computational tools consistently predict a neutral effect on the gene product.
Recorded classification: Not classified
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for ATM Version 1.5 v1.5 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting benign; maps to Uncertain Significance - Conflicting Evidence.
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
This variant is present in gnomAD v2.1 (AF= 3.98769e-06; MAF= 0.00040%, 1/250772 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.82441e-06; MAF= 0.00088%, 1/113322 alleles, homozygotes = 0).
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.
ClinVar submissions
3 reported laboratory submissions
2 Uncertain significance · 1 Likely benign. ClinVar API review status: criteria provided, conflicting classifications.
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, with the data and sources behind each one.
29 criteria with recorded statuses: 2 met · 9 not met · 0 not assessed · 18 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.7835G>A (p.Arg2612Lys) is a missense variant in ATM, a gene where loss of function is an established mechanism for ataxia telangiectasia (autosomal recessive) and ATM-related cancer predisposition (autosomal dominant). The variant is absent from gnomAD v4.1 and present at extremely low frequency in gnomAD v2.1 (1/250,772 alleles, NFE only).
PM2_Supporting is met: the variant frequency (absent from gnomAD v4.1) satisfies the VCEP threshold of ≤0.001%.
BP4_Supporting is met: REVEL score of 0.086 is ≤0.249, SpliceAI max delta of 0.0 is ≤0.1, and BayesDel score of −0.523 is in the benign range. Multiple computational tools consistently predict a neutral effect.
No functional data (PS3/BS3), segregation data (PP1), case-control data (PS4), or variant-specific publications were identified for this variant. OncoKB reports unknown oncogenic effect, and the VCEP supplementary functional tables do not include p.Arg2612Lys.
This variant has been reported in ClinVar as Uncertain significance by two clinical laboratories and as Likely benign by one clinical laboratory (Variation ID 407542). No expert panel classification is available.
Under the ClinGen HBOP ATM VCEP v1.5 combination rules, PM2_Supporting (1 pathogenic supporting) and BP4_Supporting (1 benign supporting) together trigger Rule 31: Uncertain Significance — Conflicting Evidence.
No criteria match.
Met · 2
PM2 SupportingThis variant is absent from gnomAD v4.1. Under the ATM VCEP PM2 rule, a frequency ≤0.001% in gnomAD v4 qualifies for PM2_Supporting. In gnomAD v2.1, the variant is present at extremely low frequency (AF=3.99×10⁻⁶; 1/250,772 alleles, NFE subpopulation only, no homozygotes). Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1. gnomAD v2.1: 1/250
- 772 alleles (AF=3.99×10⁻⁶)
- single NFE heterozygote. VCEP threshold ≤0.001% satisfied.
Sources
BP4 SupportingREVEL score is 0.086, which is ≤0.249 (VCEP BP4 threshold for missense variants). SpliceAI predicts no splicing impact (max delta = 0.0, which is ≤0.1). BayesDel score is −0.523 (predicted benign). Multiple independent computational tools consistently predict a neutral effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.086 (threshold ≤0.249). SpliceAI: max delta = 0.0 (threshold ≤0.1). BayesDel: −0.523 (predicted benign).
Sources
Not met · 9 · evaluated, threshold not reached
PS1 No evidence that the same amino acid change (p.Arg2612Lys) produced by a different nucleotide substitution has been classified as pathogenic or likely pathogenic. PS1 requires a known pathogenic comparator with the identical amino acid change via a different nucleotide change, and no such comparator variant is documented in the case materials. Details ▾Hide ▴
PS3 No functional data available for NM_000051.4:c.7835G>A (p.Arg2612Lys). OncoKB reports 'Unknown Oncogenic Effect' with no variant-specific functional evidence. The VCEP supplementary functional tables (Suppl_TableS1, clingen_hbop_atm kinase activity and radiosensitivity tables) do not include this variant. No publications characterizing the functional impact of this variant were identified. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence. VCEP supplementary tables: variant not listed in ATM kinase activity or radiosensitivity assays.
Still missing
- No functional studies have tested this variant or a systematically characterized range that includes position 2612.
Sources
PS4 No case-control studies or affected individual case reports featuring NM_000051.4:c.7835G>A were identified. The VCEP PS4 rule requires case-control data with p≤0.05 AND (OR≥2 or lower 95% CI ≥1.5), which is not available for this variant. Details ▾Hide ▴
PP1 No segregation data are available for this variant. The VCEP permits PP1 for AR conditions (ataxia telangiectasia) when segregation in affected relatives is demonstrated, but no such data exist in the case materials. Details ▾Hide ▴
Evidence considered
- No segregation data or family studies available.
Still missing
- No family-based segregation analysis has been performed for this variant.
PP3 REVEL score is 0.086, which is well below the VCEP PP3 threshold of >0.7333 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.0). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.086 (threshold >0.7333). SpliceAI: max delta = 0.0. BayesDel: -0.523 (predicted benign). All computational tools predict a benign effect.
Sources
BA1 The variant is absent from gnomAD v4.1. The VCEP BA1 threshold requires Grpmax Filtering AF > 0.5% in gnomAD v4, which is not met. The variant is extremely rare, appearing in only 1/250,772 alleles in gnomAD v2.1. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1. gnomAD v2.1: AF=3.99×10⁻⁶ (1/250
- 772). Far below BA1 threshold of >0.5%.
Sources
BS1 The variant is absent from gnomAD v4.1. The VCEP BS1 threshold requires Grpmax Filtering AF > 0.05% in gnomAD v4, which is not met. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v4.1. gnomAD v2.1: AF=3.99×10⁻⁶ (1/250
- 772). Far below BS1 threshold of >0.05%.
Sources
BS3 No functional data demonstrating a benign effect for NM_000051.4:c.7835G>A (p.Arg2612Lys) are available. The VCEP supplementary functional tables do not include this variant, and no publications were identified that assayed its functional impact. Details ▾Hide ▴
Evidence considered
- VCEP ATM kinase activity and radiosensitivity tables do not list p.Arg2612Lys. No functional rescue data available.
Still missing
- No functional studies have tested rescue of ATM-specific features or radiosensitivity for this variant.
Sources
vcep_suppl_tables1_pmid_40580951vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BP2 No evidence that this variant has been observed in trans with a pathogenic or likely pathogenic ATM variant in an unaffected individual aged 18 years or older. The VCEP BP2 point system requires specific proband data that are not available in the case materials. Details ▾Hide ▴
Evidence considered
- No trans or homozygous observations in unaffected individuals available.
Still missing
- No proband data with phase information in unaffected individuals.
Sources
cspec ↗vcep_atm_pm3_bp2_1_5
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_000051.4:c.7835G>A is a missense variant (p.Arg2612Lys), not a null variant (nonsense, frameshift, or canonical splice site). The ATM VCEP PVS1 decision tree applies only to null variant types; missense variants are not eligible for PVS1. Details ▾Hide ▴
Evidence considered
- Missense variant
- variant bucket classified as 'other' by generic PVS1 framework. ATM VCEP PVS1 decision tree does not apply to missense substitutions.
Sources
pvs1_generic_framework ↗vcep_atm_pvs1_1_5
PS2 VCEPATM VCEP v1.5 does not permit use of PS2: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.' Details ▾Hide ▴
PM1 VCEPATM VCEP v1.5 does not permit use of PM1: 'Do not use: Benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time.' Details ▾Hide ▴
PM3 N/ASkipped per user instruction. Details ▾Hide ▴
Evidence considered
- Skipped.
PM4 N/ASkipped per user instruction. ATM VCEP also restricts PM4 to stop-loss variants only; this is a missense substitution. Details ▾Hide ▴
Evidence considered
- Skipped.
PM5 N/AATM VCEP restricts PM5 to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, and to splice variants where PVS1_VS(RNA) is applied. Missense changes are explicitly excluded: 'Do not use for missense changes: Multiple amino acid substitutions at the same residue can be pathogenic or benign and bioinformatic tools cannot yet confidently distinguish them.' Details ▾Hide ▴
Evidence considered
- VCEP PM5 rule excludes missense variants. This variant is a missense substitution (p.Arg2612Lys).
Sources
cspec ↗pm5_candidates
PM6 VCEPATM VCEP v1.5 does not permit use of PM6: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.' Details ▾Hide ▴
PP2 VCEPATM VCEP v1.5 does not permit use of PP2: 'Do not use: ATM does not have a defined low rate of missense benign variation.' Details ▾Hide ▴
PP4 VCEPATM VCEP v1.5 does not permit use of PP4: 'Autosomal Dominant: do not use as breast cancer is a disease with multiple genetic etiology... Autosomal Recessive: do not use as a separate line of evidence. Such evidence is built into the Ataxia Telangiectasia PM3|BP2 table.' Details ▾Hide ▴
PP5 VCEPATM VCEP v1.5 does not permit use of PP5: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' ClinVar classification is 'Uncertain significance' with review status 'criteria provided, single submitter' — not an expert panel classification that would trigger PP5 even under generic override rules. Details ▾Hide ▴
BS2 VCEPATM VCEP v1.5 does not permit use of BS2: 'Do not use: ATM has incomplete penetrance.' Details ▾Hide ▴
BS4 VCEPATM VCEP v1.5 does not permit use of BS4: 'AD Condition: Co-segregation analysis in low penetrance genes can lead to false positive results. AR Condition: Informative instances of lack of co-segregation in A-T families are too rare.' Details ▾Hide ▴
BP1 VCEPATM VCEP v1.5 does not permit use of BP1: 'Do not use: Missense pathogenic variants are known for ATM.' Details ▾Hide ▴
BP3 VCEPSkipped per user instruction. ATM VCEP v1.5 also marks BP3 as Not Applicable. Details ▾Hide ▴
Evidence considered
- Skipped.
BP5 VCEPATM VCEP v1.5 does not permit use of BP5: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype.' Details ▾Hide ▴
BP6 VCEPATM VCEP v1.5 does not permit use of BP6: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' ClinVar classification is 'Uncertain significance' with review status 'criteria provided, single submitter' — not an expert panel benign classification. Details ▾Hide ▴
BP7 N/ABP7 under the ATM VCEP is applicable only to synonymous and deep intronic variants. NM_000051.4:c.7835G>A is a missense variant (p.Arg2612Lys) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous and deep intronic variants per VCEP.
Sources
PS5 N/APS5 is not a criterion in the standard ACMG/AMP 2015 framework. The recognized pathogenic criteria are PVS1, PS1, PS2, PS3, PS4, PM1, PM2, PM3, PM4, PM5, PM6, PP1, PP2, PP3, PP4, and PP5. Details ▾Hide ▴
Evidence considered
- PS5 does not exist in the ACMG/AMP framework.
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.7835G>A
- Protein (HGVS p.)
- NP_000042.3:p.(Arg2612Lys)
- GRCh38
- chr11:108332808 G>A
- GRCh37
- chr11:108203535 G>A
- ClinVar
- 407542
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
Allele count data not recorded
gnomAD v2.1
1 / 250,772 alleles
AF 3.99e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v2.1
AF 4e-06 · 1 / 250,772 alleles · 0 hom
| European (non-Finnish)1 / 113,322 | 8.8e-06 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.98769e-06; MAF= 0.00040%, 1/250772 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.82441e-06; MAF= 0.00088%, 1/113322 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.086
- BayesDel
- -0.523
How the predictions were used
BP4 SupportingREVEL score is 0.086, which is ≤0.249 (VCEP BP4 threshold for missense variants). SpliceAI predicts no splicing impact (max delta = 0.0, which is ≤0.1). BayesDel score is −0.523 (predicted benign). Multiple independent computational tools consistently predict a neutral effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL: 0.086 (threshold ≤0.249). SpliceAI: max delta = 0.0 (threshold ≤0.1). BayesDel: −0.523 (predicted benign).
Sources
PP3 REVEL score is 0.086, which is well below the VCEP PP3 threshold of >0.7333 for missense variants. SpliceAI predicts no splicing impact (max delta = 0.0). Computational evidence does not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.086 (threshold >0.7333). SpliceAI: max delta = 0.0. BayesDel: -0.523 (predicted benign). All computational tools predict a benign effect.
Sources
BP7 N/ABP7 under the ATM VCEP is applicable only to synonymous and deep intronic variants. NM_000051.4:c.7835G>A is a missense variant (p.Arg2612Lys) and does not qualify for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is restricted to synonymous and deep intronic variants per VCEP.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.086. BayesDel score = -0.523282.
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
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PMID 20301317 ↗Hereditary Ataxia Overview.Adam MP et al. · 1993GeneReviews overview of hereditary ataxias. Provides general clinical and genetic context for ATM-related ataxia telangiectasia but does not discuss NM_000051.4:c.7835G>A (p.Arg2612Lys).Does not name this variant
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PMID 20301790 ↗Ataxia-Telangiectasia.Adam MP et al. · 1993GeneReviews entry for ataxia-telangiectasia. Summarizes clinical characteristics, diagnosis, and management of A-T but does not mention NM_000051.4:c.7835G>A (p.Arg2612Lys).Does not name this variant
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PMID 24418350 ↗EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.van de Warrenburg BP et al. · 2014EFNS/ENS consensus guideline on diagnosis and management of chronic ataxias in adulthood. Provides disease-level guidance but does not mention NM_000051.4:c.7835G>A (p.Arg2612Lys).Does not name this variant
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PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015ACMG/NSGC practice guideline on referral indications for cancer predisposition assessment. General clinical guidance document that does not discuss NM_000051.4:c.7835G>A (p.Arg2612Lys).Does not name this variant
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PMID 20050888 ↗EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.Gasser T et al. · 2010EFNS guidelines on molecular diagnosis of ataxias and spastic paraplegias. Reviews molecular diagnostic approaches but does not discuss NM_000051.4:c.7835G>A (p.Arg2612Lys).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
2 Uncertain significance · 1 Likely 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/407542/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108203535-G-A?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108332808-G-A?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-108332808-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.7835…
- OncoKB ↗www.oncokb.org/gene/ATM/R2612K
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.7835G%3EA
- 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
This variant is present in gnomAD v2.1 (AF= 3.98769e-06; MAF= 0.00040%, 1/250772 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.82441e-06; MAF= 0.00088%, 1/113322 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (2 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 407542)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.086. BayesDel score = -0.523282.
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.