About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.7486G>C, p.(Gly2496Arg)
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 v1.5.0. 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: 1
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
NM_000051.4:c.7486G>C is extremely rare in population databases. In gnomAD v4.1, the variant is present at an allele frequency of 0.00037% (6/1,614,098 alleles, 0 homozygotes), with a grpmax filtering AF of 1.83e-06. This frequency (≤0.001%) meets the ATM VCEP threshold for PM2_Supporting.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
BP4 for missense variants under ATM VCEP requires REVEL score ≤0.249. The REVEL score for NM_000051.4:c.7486G>C is 0.189, meeting this threshold. Additionally, BayesDel score is negative (-0.183511) and SpliceAI max delta is 0.04 (≤0.1), indicating no predicted splicing impact. Multiple lines of computational evidence suggest no damaging effect on the gene product.
Recorded classification: Not classified
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule31 (Benign.Supporting >=1 + Pathogenic.Supporting >=1) with applied criteria: PM2 supporting, BP4 supporting; 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
6 / 1,614,098 alleles
gnomAD v4.1: 6 / 1,614,098 alleles. Recorded AF 3.71725e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.040 maximum delta
Recorded SpliceAI maximum delta score: 0.040. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
3 reported laboratory submissions
3 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.
29 criteria with recorded statuses: 2 met · 6 not met · 3 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.7486G>C (p.Gly2496Arg) is a missense variant in ATM exon 50.
This variant is extremely rare in population databases: present in gnomAD v4.1 at an allele frequency of 0.00037% (6/1,614,098 alleles, 0 homozygotes), meeting the VCEP threshold for PM2_Supporting.
Multiple lines of computational evidence suggest a benign effect: REVEL score is 0.189 (meeting the VCEP BP4 threshold of ≤0.249), BayesDel score is negative (-0.183511), and SpliceAI predicts no splicing impact (max delta 0.04). BP4_Supporting is applied.
The ATM VCEP supplementary in silico meta-predictor (Suppl_TableS1, PMID:40580951) classifies this variant as 'Functional' with High confidence (Combined score 0.962), consistent with the benign computational evidence.
This variant has been reported in ClinVar as Uncertain significance by three clinical laboratories (Variation ID: 569749).
PVS1, PS1, PM1, PM5, PM6, PS2, PP1, PP2, PP4, PP5, BS2, BS4, BP1, BP5, BP6, and BP7 are not applicable per ATM VCEP v1.5.0 specifications.
No variant-specific experimental functional studies, case-control data, or segregation data were identified for this variant.
Applying the ATM VCEP v1.5.0 classification framework: PM2_Supporting (1 pathogenic supporting point) and BP4_Supporting (1 benign supporting point). Per the generic ACMG/AMP 2015 combination rules (Rule 31), one pathogenic supporting criterion and one benign supporting criterion result in conflicting evidence, yielding an overall classification of Uncertain Significance.
No criteria match.
Met · 2
PM2 SupportingNM_000051.4:c.7486G>C is extremely rare in population databases. In gnomAD v4.1, the variant is present at an allele frequency of 0.00037% (6/1,614,098 alleles, 0 homozygotes), with a grpmax filtering AF of 1.83e-06. This frequency (≤0.001%) meets the ATM VCEP threshold for PM2_Supporting. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 6/1
- 614
- 098 alleles (AF=3.72e-06
- 0.00037%)
- grpmax FAF=1.83e-06. Absent from gnomAD v2.1 and gnomAD-Canada.
Sources
BP4 SupportingBP4 for missense variants under ATM VCEP requires REVEL score ≤0.249. The REVEL score for NM_000051.4:c.7486G>C is 0.189, meeting this threshold. Additionally, BayesDel score is negative (-0.183511) and SpliceAI max delta is 0.04 (≤0.1), indicating no predicted splicing impact. Multiple lines of computational evidence suggest no damaging effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL=0.189 (≤0.249 threshold met)
- BayesDel=-0.183511
- SpliceAI max delta=0.04 (≤0.1
- no predicted splice impact).
Sources
Not met · 6 · evaluated, threshold not reached
PS1 PS1 requires a previously established pathogenic or likely pathogenic variant causing the same amino acid change. The only other variant at this residue yielding Gly2496Arg is NM_000051.4:c.7486G>A, which is classified as Uncertain significance in ClinVar and is not an established P/LP variant. No P/LP variant with the same amino acid change was identified. Details ▾Hide ▴
Evidence considered
- c.7486G>A (also G2496R) is classified as Uncertain significance
- not a P/LP reference variant for PS1.
Sources
vcep_atm_ps1_1_5vcep_suppl_tables1_pmid_40580951
PS4 PS4 requires case-control studies demonstrating statistically significant enrichment of the variant in affected individuals (p≤0.05, OR/HR/RR ≥2 or lower 95% CI ≥1.5). None of the publications associated with this case provide case-control data for this variant. The ClinVar-associated PMIDs are general reviews, guidelines, or methodological papers that do not contain variant-specific prevalence or enrichment data. Details ▾Hide ▴
Evidence considered
- No case-control studies available. PMIDs from ClinVar are reviews/guidelines without variant-specific enrichment data.
Still missing
- No case-control data for this variant.
Sources
PP1 PP1 requires co-segregation of the variant with disease in affected family members. For ATM (AR condition), this requires both variants to be identified in affected relatives. No segregation data were identified in any of the reviewed publications or evidence sources. Details ▾Hide ▴
Evidence considered
- No segregation data available for this variant.
Still missing
- No family segregation studies available.
PP3 PP3 for missense variants under ATM VCEP requires REVEL score >0.7333. The REVEL score for this variant is 0.189, which does not meet this threshold. SpliceAI max delta score is 0.04 (<0.2), indicating no predicted splicing impact. Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.189 (threshold >0.7333 not met)
- BayesDel=-0.183511 (negative score)
- SpliceAI max delta=0.04 (<0.2).
Sources
BA1 BA1 requires grpmax filtering AF >0.5% in gnomAD v4. The variant's grpmax FAF is 1.83e-06 (0.000183%), far below the 0.5% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4 grpmax FAF=1.83e-06 (0.000183%)
- threshold >0.5% not met.
Sources
BS1 BS1 requires grpmax filtering AF >0.05% in gnomAD v4. The variant's grpmax FAF is 1.83e-06 (0.000183%), far below the 0.05% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4 grpmax FAF=1.83e-06 (0.000183%)
- threshold >0.05% not met.
Sources
Not assessed · 3 · no assessment recorded
PS3 No variant-specific experimental functional studies (well-established in vitro or in vivo assays) were identified for NM_000051.4:c.7486G>C. The VCEP supplementary spreadsheet (Suppl_TableS1, PMID:40580951) provides an in silico meta-prediction classifying this variant as 'Functional' (Combined score 0.962, High confidence), but this represents computational prediction rather than experimental functional evidence. No published functional assay data (kinase activity, radiosensitivity, or ATM-specific phosphorylation rescue) were found for this variant. Details ▾Hide ▴
Evidence considered
- VCEP in silico meta-predictor classifies variant as 'Functional' (High confidence)
- OncoKB reports no variant-specific reviewed functional evidence.
Still missing
- No variant-specific experimental functional studies available. ATM kinase assay or radiosensitivity rescue data would be needed to apply PS3.
Sources
vcep_suppl_tables1_pmid_40580951oncokb ↗
BS3 No variant-specific experimental functional studies demonstrating no damaging effect were identified for NM_000051.4:c.7486G>C. The VCEP supplementary spreadsheet (Suppl_TableS1, PMID:40580951) classifies this variant as 'Functional' (Combined score 0.962, High confidence) based on in silico meta-prediction, but this computational prediction does not constitute well-established in vitro or in vivo functional evidence as required for BS3. No published functional rescue data (kinase activity, radiosensitivity) were identified for this variant. Details ▾Hide ▴
Evidence considered
- VCEP in silico meta-predictor classifies variant as 'Functional' (High confidence)
- no experimental functional rescue studies available.
Still missing
- No variant-specific experimental functional studies demonstrating normal protein function. ATM kinase assay or radiosensitivity rescue data would be needed to apply BS3.
Sources
vcep_suppl_tables1_pmid_40580951oncokb ↗
BP2 BP2 requires observation of the variant in trans with a pathogenic variant in an unaffected individual (≥18 years, no evidence of A-T). No such data were identified in the available evidence. No proband data for PM3/BP2 point assignment were found. Details ▾Hide ▴
Evidence considered
- No trans-phase or homozygous unaffected individual data available for BP2 point assignment.
Still missing
- No proband-level data for PM3/BP2 point assignment.
Sources
vcep_atm_pm3_bp2_1_5
Not applicable · 18· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is applicable only to null variants (nonsense, frameshift, canonical splice sites, initiation codon, exon deletions). NM_000051.4:c.7486G>C is a missense variant (p.Gly2496Arg) and does not meet the variant-type prerequisites for PVS1 under the ATM VCEP PVS1 decision tree. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not a null variant eligible for PVS1.
Sources
pvs1_variant_assessmentvcep_atm_pvs1_1_5
PS2 VCEPPS2 is not applicable per ATM VCEP v1.5.0: informative de novo occurrences have not yet been observed for ATM and de novo AR conditions are unlikely to be informed by phase. Details ▾Hide ▴
PM1 VCEPPM1 is not applicable per ATM VCEP v1.5.0. The VCEP states: '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/APM3 is skipped per adjudication instructions. No trans-phase data were collected for PM3/BP2 point assignment in this assessment run. Details ▾Hide ▴
Evidence considered
- Skipped per instructions
- trivially not_applicable.
PM4 N/APM4 is skipped per adjudication instructions. NM_000051.4:c.7486G>C is a missense substitution; PM4 applies only to in-frame deletions/insertions and stop-loss variants per ATM VCEP. Details ▾Hide ▴
PM5 N/APM5 per ATM VCEP v1.5.0 applies only to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants meeting specific criteria. The VCEP explicitly states: 'Do not use for missense changes.' NM_000051.4:c.7486G>C is a missense variant. Details ▾Hide ▴
Evidence considered
- Missense variant
- PM5 not applicable per VCEP as it applies only to truncating/frameshift/splice variants.
Sources
cspec ↗pm5_candidates
PM6 VCEPPM6 is not applicable per ATM VCEP v1.5.0: '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 VCEPPP2 is not applicable per ATM VCEP v1.5.0: 'Do not use: ATM does not have a defined low rate of missense benign variation.' Details ▾Hide ▴
PP4 VCEPPP4 is not applicable per ATM VCEP v1.5.0: for autosomal dominant (breast cancer), do not use due to genetic heterogeneity; for autosomal recessive, such evidence is built into the PM3/BP2 table. Details ▾Hide ▴
PP5 VCEPPP5 is not applicable per ATM VCEP v1.5.0: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
BS2 VCEPBS2 is not applicable per ATM VCEP v1.5.0: 'Do not use: ATM has incomplete penetrance.' Details ▾Hide ▴
BS4 VCEPBS4 is not applicable per ATM VCEP v1.5.0: for AD (cancer), co-segregation analysis in low-penetrance genes can lead to false positives; for AR (A-T), informative instances of lack of co-segregation are too rare to be considered for weight. Details ▾Hide ▴
BP1 VCEPBP1 is not applicable per ATM VCEP v1.5.0: 'Do not use: Missense pathogenic variants are known for ATM.' Details ▾Hide ▴
BP3 VCEPBP3 is not applicable per ATM VCEP v1.5.0. This criterion applies to in-frame deletions/insertions in repetitive regions without known function; not relevant to a missense substitution. Details ▾Hide ▴
BP5 VCEPBP5 is not applicable per ATM VCEP v1.5.0: 'Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype. In addition, ATM has low penetrance and will naturally occur with other pathogenic variants more frequently.' Details ▾Hide ▴
BP6 VCEPBP6 is not applicable per ATM VCEP v1.5.0: 'This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.' Details ▾Hide ▴
BP7 N/ABP7 applies to synonymous variants and deep intronic variants. NM_000051.4:c.7486G>C is a missense variant (p.Gly2496Arg) and does not meet the variant-type requirements for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous and deep intronic variants only.
Sources
PS5 N/APS5 is not a standard ACMG/AMP criterion. No such criterion exists in the ACMG/AMP 2015 guidelines or the ATM VCEP v1.5.0 specifications. Details ▾Hide ▴
Evidence considered
- Not a valid ACMG/AMP criterion.
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.7486G>C
- Protein (HGVS p.)
- NP_000042.3:p.(Gly2496Arg)
- GRCh38
- chr11:108330392 G>C
- GRCh37
- chr11:108201119 G>C
- ClinVar
- 569749
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
6 / 1,614,098 alleles
AF 3.72e-06 · 0 homozygotes · FAF 1.83e-06
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.7e-06 · 6 / 1,614,098 alleles · 0 hom · FAF 1.8e-06
| European (non-Finnish)6 / 1,179,994 | 5.1e-06 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 3.71725e-06; MAF= 0.00037%, 6/1614098 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08477e-06; MAF= 0.00051%, 6/1179994 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.189
- BayesDel
- -0.184
How the predictions were used
BP4 SupportingBP4 for missense variants under ATM VCEP requires REVEL score ≤0.249. The REVEL score for NM_000051.4:c.7486G>C is 0.189, meeting this threshold. Additionally, BayesDel score is negative (-0.183511) and SpliceAI max delta is 0.04 (≤0.1), indicating no predicted splicing impact. Multiple lines of computational evidence suggest no damaging effect on the gene product. Details ▾Hide ▴
Evidence considered
- REVEL=0.189 (≤0.249 threshold met)
- BayesDel=-0.183511
- SpliceAI max delta=0.04 (≤0.1
- no predicted splice impact).
Sources
PP3 PP3 for missense variants under ATM VCEP requires REVEL score >0.7333. The REVEL score for this variant is 0.189, which does not meet this threshold. SpliceAI max delta score is 0.04 (<0.2), indicating no predicted splicing impact. Multiple lines of computational evidence do not support a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL=0.189 (threshold >0.7333 not met)
- BayesDel=-0.183511 (negative score)
- SpliceAI max delta=0.04 (<0.2).
Sources
BP7 N/ABP7 applies to synonymous variants and deep intronic variants. NM_000051.4:c.7486G>C is a missense variant (p.Gly2496Arg) and does not meet the variant-type requirements for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 is for synonymous and deep intronic variants only.
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.189. BayesDel score = -0.183511.
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. NM_000051.4:c.7486G>C is not mentioned.Does not name this variant
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PMID 20301790 ↗Ataxia-Telangiectasia.Adam MP et al. · 1993GeneReviews overview of Ataxia-Telangiectasia covering clinical characteristics, genetics, and management. NM_000051.4:c.7486G>C is not mentioned.Does not name this variant
-
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. NM_000051.4:c.7486G>C is not mentioned.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. NM_000051.4:c.7486G>C is not mentioned.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. NM_000051.4:c.7486G>C is 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
6 / 1,614,098 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
3 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/569749/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108201119-G-C?dataset=gnom…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108330392-G-C?dataset=g…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-108330392-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.7486…
- OncoKB ↗www.oncokb.org/gene/ATM/G2496R
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.7486G%3EC
- 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= 3.71725e-06; MAF= 0.00037%, 6/1614098 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08477e-06; MAF= 0.00051%, 6/1179994 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
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 (3 clinical laboratories). (ClinVarID = 569749)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04). REVEL score = 0.189. BayesDel score = -0.183511.
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.