About ATM
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
ATM c.662+13_662+14del, p.?
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely 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: 1
Benign evidence criteria: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
Per ATM VCEP v1.5.0, PM2_Supporting applies when frequency is <=0.001% in gnomAD v4. This variant is present at extremely low frequency in gnomAD v4.1 (AF=1.24e-06, 0.000124%, 2/1,613,430 alleles, 0 homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada. The frequency is well below the 0.001% threshold.
Benign criteria applied · 2
BP4Supporting
BP4 · supporting
Per ATM VCEP v1.5.0, BP4 for splicing applies when SpliceAI <=0.1, indicating no predicted impact via splicing. SpliceAI max delta score for this variant is 0.05, which falls below the 0.1 threshold. Multiple lines of computational evidence (SpliceAI) suggest no impact on splicing.
BP7Supporting
BP7 · supporting
Per ATM VCEP v1.5.0, BP7 applies to deep intronic variants defined as further than (but not including) +7 at donor sites. This variant is at position +13/+14 of the intron 6 donor site, which is beyond +7. SpliceAI predicts no significant splice impact (max delta=0.05). No aberrant RNA defect has been observed.
Recorded classification: Likely benign
Richards et.al., 2015 - Combining rules v1.5.0 criteria-combination framework: matched Rule19 (Benign.Supporting >=2) with applied criteria: PM2 supporting, BP4 supporting, BP7 supporting; maps to Likely 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
2 / 1,613,430 alleles
gnomAD v4.1: 2 / 1,613,430 alleles. Recorded AF 1.2396e-06. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.050 maximum delta
Recorded SpliceAI maximum delta score: 0.050. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
Context only
ClinVar ↗
No screenshot for this evidence
Functional evidence
Not recorded
No standalone functional evidence summary is recorded in evidence_summary.functional.
No listed criterion applied
OncoKB ↗
Somatic evidence
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
Context only
COSMIC ↗
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: 3 met · 11 not met · 0 not assessed · 14 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.662+13_662+14del is an intronic deletion in ATM at positions +13 and +14 of the intron 6 donor site, outside the canonical +/-1,2 splice consensus.
SpliceAI predicts no significant splice impact (max delta score=0.05), indicating this variant is unlikely to disrupt normal ATM mRNA splicing.
The variant is present at extremely low frequency in gnomAD v4.1 (2/1,613,430 alleles; AF=1.24e-06; 0.000124%), meeting ATM VCEP PM2_Supporting criteria (<=0.001%).
The variant is absent from gnomAD v2.1 and gnomAD-Canada v1.0, and absent from ClinVar classifications.
As an intronic variant beyond +7 with no predicted splice impact, BP7 (deep intronic, supporting) and BP4 (no predicted splicing impact, supporting) both apply per ATM VCEP v1.5.0.
No functional studies (PS3/BS3), segregation data (PP1), case-control studies (PS4), or phase observations (PM3/BP2) are available for this variant.
No criteria match.
Met · 3
PM2 SupportingPer ATM VCEP v1.5.0, PM2_Supporting applies when frequency is <=0.001% in gnomAD v4. This variant is present at extremely low frequency in gnomAD v4.1 (AF=1.24e-06, 0.000124%, 2/1,613,430 alleles, 0 homozygotes) and is absent from gnomAD v2.1 and gnomAD-Canada. The frequency is well below the 0.001% threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=1.24e-06 (0.000124%)
- 2/1
- 613
- 430 alleles
- 0 homozygotes
- gnomAD v2.1: absent
- gnomAD-Canada v1.0: absent
Sources
BP4 SupportingPer ATM VCEP v1.5.0, BP4 for splicing applies when SpliceAI <=0.1, indicating no predicted impact via splicing. SpliceAI max delta score for this variant is 0.05, which falls below the 0.1 threshold. Multiple lines of computational evidence (SpliceAI) suggest no impact on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.05 (<=0.1 threshold for BP4)
Sources
BP7 SupportingPer ATM VCEP v1.5.0, BP7 applies to deep intronic variants defined as further than (but not including) +7 at donor sites. This variant is at position +13/+14 of the intron 6 donor site, which is beyond +7. SpliceAI predicts no significant splice impact (max delta=0.05). No aberrant RNA defect has been observed. Details ▾Hide ▴
Evidence considered
- Variant located at +13/+14 of intron 6 donor site (deep intronic
- beyond +7)
- SpliceAI max delta score = 0.05 (no predicted splice impact)
Still missing
- No RNA functional data to confirm absence of aberrant splicing
Sources
Not met · 11 · evaluated, threshold not reached
PVS1 NM_000051.4:c.662+13_662+14del is an intronic deletion at positions +13 and +14 of the intron 6 donor site, outside the canonical +/-1,2 splice consensus. Per the ATM VCEP v1.5.0 PVS1 decision tree, PVS1 for intronic variants outside the canonical splice dinucleotide requires a predicted or observed splicing defect. SpliceAI predicts no significant splice impact (max delta score=0.05), falling below the PP3 threshold of >=0.2. No RNA functional data demonstrating aberrant splicing are available. PVS1 is therefore not met. Details ▾Hide ▴
Evidence considered
- Variant is intronic at +13/+14 of donor site
- outside canonical +/-1
- 2 splice consensus
- SpliceAI max delta score = 0.05 (no predicted splice impact)
- ATM VCEP PVS1 decision tree requires predicted or observed splice defect for intronic variants outside +/-1
- 2
Still missing
- No RNA functional study (patient RNA or minigene assay) evaluating splicing effects for this exact variant
Sources
PS1 Per the ATM VCEP v1.5.0 PS1 splicing table, PS1 requires a known pathogenic or likely pathogenic reference variant at the same nucleotide position with similar or stronger computational prediction of the same splicing outcome. No pathogenic/likely pathogenic comparator variant has been identified at c.662+13_662+14 in ClinVar or the VCEP reference datasets. No reference variant is available for PS1 comparison. Details ▾Hide ▴
Evidence considered
- Variant located outside donor/acceptor +/-1
- 2 dinucleotide positions
- baseline computational code is PP3
- No P/LP reference variant identified at c.662+13_662+14 for PS1 comparator analysis
Still missing
- No pathogenic reference variant at c.662+13_662+14 in ClinVar or literature
Sources
PS3 Per ATM VCEP v1.5.0, PS3 requires functional studies demonstrating a damaging effect on ATM-specific features (e.g., phosphorylation of ATM-specific targets) with or without radiosensitivity rescue failure. No functional study assessing this exact variant was identified in the VCEP functional dataset (Suppl_TableS1_PMID_40580951) or in the literature. The variant is an intronic deletion and is not represented in the ATM missense functional catalog. Details ▾Hide ▴
Evidence considered
- Variant absent from ATM VCEP functional dataset (Suppl_TableS1
- PMID:40580951)
- No published functional assay (biochemical
- RNA
- protein
- or cellular phenotype) for this variant
Still missing
- No functional study evaluating ATM kinase activity or radiosensitivity for this variant
Sources
PS4 Per ATM VCEP v1.5.0, PS4_Strong requires case-control studies with p-value <=0.05 and OR/HR/RR >=2 or lower 95% CI >=1.5. No case-control study or proband enrichment data have been published for this variant. The variant is extremely rare (gnomAD v4.1 AF=1.24e-06) and absent from ClinVar submissions with clinical assertions. Details ▾Hide ▴
Evidence considered
- No case-control study identified for this variant
- gnomAD v4.1: 2/1
- 613
- 430 alleles (AF=1.24e-06)
- ClinVar: absent (no clinical submissions with classification)
Still missing
- No case-control or cohort enrichment data available
Sources
PP1 Per ATM VCEP v1.5.0, PP1 for autosomal recessive conditions requires co-segregation in affected relatives with both variants identified in the proband. No family-based segregation analysis or linkage data have been published for this variant. Details ▾Hide ▴
Evidence considered
- No co-segregation or family linkage data found for this variant
Still missing
- No published family studies or segregation data
Sources
PP3 Per ATM VCEP v1.5.0, PP3 for splicing requires SpliceAI >=0.2 for intronic variants outside donor/acceptor +/-1,2 sites. SpliceAI predicts no significant splice impact for this variant (max delta score=0.05), which is below the 0.2 threshold. Additionally, VCEP guidance states PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes. REVEL/BayesDel scores are not applicable to this intronic deletion. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.05 (below PP3 threshold of >=0.2)
- No other computational evidence supporting a deleterious effect
Sources
BA1 Per ATM VCEP v1.5.0, BA1 requires Grpmax Filtering AF >0.5% in gnomAD v4. This variant is extremely rare (AF=1.24e-06, 0.000124% in gnomAD v4.1), far below the 0.5% BA1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=1.24e-06 (0.000124%)
- far below BA1 threshold of >0.5%
Sources
BS1 Per ATM VCEP v1.5.0, BS1 requires Grpmax Filtering AF >0.05% in gnomAD v4. This variant is extremely rare (AF=1.24e-06, 0.000124% in gnomAD v4.1), far below the 0.05% BS1 threshold. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: AF=1.24e-06 (0.000124%)
- far below BS1 threshold of >0.05%
Sources
BS3 Per ATM VCEP v1.5.0, BS3 requires functional studies showing rescue of ATM-specific features and/or radiosensitivity. No functional study demonstrating a benign effect (normal splicing, protein expression, or kinase activity) has been identified for this variant. The variant is absent from the VCEP functional dataset (Suppl_TableS1, PMID:40580951). Details ▾Hide ▴
Evidence considered
- Variant absent from ATM VCEP functional dataset
- No published functional assay showing benign effect
Still missing
- No functional study demonstrating normal splicing or preserved ATM activity
Sources
BP2 Per ATM VCEP v1.5.0, BP2 requires observation of the variant in cis with a pathogenic ATM variant, or in trans with a P/LP variant in an unaffected individual aged 18+ without evidence of A-T. No such observation has been reported for this variant in ClinVar or the literature. Details ▾Hide ▴
PS5 No reputable source has reported this variant as pathogenic. The variant is absent from ClinVar classifications and no published clinical report asserts pathogenicity. Details ▾Hide ▴
Evidence considered
- Variant absent from ClinVar (no classification from any submitter)
- No published clinical report asserting pathogenicity
Sources
Not applicable · 14· recorded as not applicable Show reasons ▾Hide reasons ▴
PS2 VCEPATM VCEP v1.5.0: PS2 is not applicable 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 v1.5.0: PM1 is not applicable. 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 ▴
PM4 N/AATM VCEP v1.5.0: PM4 is restricted to stop-loss variants only. This is a small intronic deletion and does not meet the VCEP PM4 criteria. Details ▾Hide ▴
Evidence considered
- VCEP restricts PM4 to stop-loss variants only
- this is an intronic deletion
Sources
PM5 N/AATM VCEP v1.5.0: PM5_Supporting applies to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or splice variants where PVS1_VS(RNA) is applied based on high-quality observed splicing impact and must be NMD-prone. This variant is an intronic deletion with no predicted splice defect (SpliceAI=0.05) and no premature termination codon; PVS1 has not been applied. PM5 is not applicable. Details ▾Hide ▴
Evidence considered
- Intronic variant with no PTC and no PVS1 applied
- SpliceAI max delta=0.05 (no predicted splice impact)
Sources
PM6 VCEPATM VCEP v1.5.0: PM6 is not applicable for AD or AR disease. Informative de novo occurrences have not yet been observed. Details ▾Hide ▴
PP2 VCEPATM VCEP v1.5.0: PP2 is not applicable. ATM does not have a defined low rate of missense benign variation. Details ▾Hide ▴
PP4 VCEPATM VCEP v1.5.0: PP4 is not applicable. For autosomal dominant disease, breast cancer has multiple genetic etiologies and no features readily distinguish hereditary from sporadic causes. For autosomal recessive disease, such evidence is built into the Ataxia Telangiectasia PM3/BP2 table. Details ▾Hide ▴
PP5 VCEPATM VCEP v1.5.0: PP5 is not applicable for this VCEP per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
BS2 VCEPATM VCEP v1.5.0: BS2 is not applicable. ATM has incomplete penetrance. Details ▾Hide ▴
BS4 VCEPATM VCEP v1.5.0: BS4 is not applicable. For autosomal dominant disease, co-segregation analysis in low-penetrance genes can lead to false positive results. For autosomal recessive disease, informative instances of lack of co-segregation in A-T families are too rare. Details ▾Hide ▴
BP1 VCEPATM VCEP v1.5.0: BP1 is not applicable. Missense pathogenic variants are known for ATM. Details ▾Hide ▴
BP3 VCEPATM VCEP v1.5.0: BP3 is not applicable; the VCEP instructs not to use this criterion. Details ▾Hide ▴
BP5 VCEPATM VCEP v1.5.0: BP5 is not applicable. Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance. Details ▾Hide ▴
BP6 VCEPATM VCEP v1.5.0: BP6 is not applicable for this VCEP per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Identifiers
- Gene
- ATM
- Transcript
- NM_000051.4
- Coding (HGVS c.)
- NM_000051.4:c.662+13_662+14del
- Protein (HGVS p.)
- NP_000042.3:p.?
- GRCh38
- chr11:108244127 ATC>A
- GRCh37
- chr11:108114854 ATC>A
- ClinVar
- 421805
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
2 / 1,613,430 alleles
AF 1.24e-06 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 1.2e-06 · 2 / 1,613,430 alleles · 0 hom
| African/African American1 / 74,874 | 1.3e-05 |
| European (non-Finnish)1 / 1,179,730 | 8.5e-07 |
0 alternate alleles recorded in 8 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 1.2396e-06; MAF= 0.00012%, 2/1613430 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33558e-05; MAF= 0.00134%, 1/74874 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- Not available
- BayesDel
- Not available
How the predictions were used
BP4 SupportingPer ATM VCEP v1.5.0, BP4 for splicing applies when SpliceAI <=0.1, indicating no predicted impact via splicing. SpliceAI max delta score for this variant is 0.05, which falls below the 0.1 threshold. Multiple lines of computational evidence (SpliceAI) suggest no impact on splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.05 (<=0.1 threshold for BP4)
Sources
BP7 SupportingPer ATM VCEP v1.5.0, BP7 applies to deep intronic variants defined as further than (but not including) +7 at donor sites. This variant is at position +13/+14 of the intron 6 donor site, which is beyond +7. SpliceAI predicts no significant splice impact (max delta=0.05). No aberrant RNA defect has been observed. Details ▾Hide ▴
Evidence considered
- Variant located at +13/+14 of intron 6 donor site (deep intronic
- beyond +7)
- SpliceAI max delta score = 0.05 (no predicted splice impact)
Still missing
- No RNA functional data to confirm absence of aberrant splicing
Sources
PP3 Per ATM VCEP v1.5.0, PP3 for splicing requires SpliceAI >=0.2 for intronic variants outside donor/acceptor +/-1,2 sites. SpliceAI predicts no significant splice impact for this variant (max delta score=0.05), which is below the 0.2 threshold. Additionally, VCEP guidance states PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes. REVEL/BayesDel scores are not applicable to this intronic deletion. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta score = 0.05 (below PP3 threshold of >=0.2)
- No other computational evidence supporting a deleterious effect
Sources
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
8 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
-
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.Richards S et al. · 2015This is the ACMG/AMP 2015 standards and guidelines for sequence variant interpretation. It provides the general framework for variant classification but does not discuss any specific ATM variants or the c.662+13_662+14del variant.Does not name this variant
-
PMID 20301317 ↗Hereditary Ataxia Overview.Adam MP et al. · 1993GeneReviews overview of hereditary ataxia. Provides broad clinical context for ataxia disorders including A-T but does not discuss specific ATM variants.Does not name this variant
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PMID 20301790 ↗Ataxia-Telangiectasia.Adam MP et al. · 1993GeneReviews chapter on Ataxia-Telangiectasia providing clinical overview of ATM-related disease. Discusses ATM gene and disease at a general level without mention of the c.662+13_662+14del variant.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 clinical diagnostic criteria for ataxia disorders without discussion of specific ATM variants.Does not name this variant
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PMID 26389258 ↗Cancer Genetics Risk Assessment and Counseling (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ cancer genetics risk assessment and counseling summary. Discusses general cancer genetics principles without mention of specific ATM variants.Does not name this variant
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PMID 26389505 ↗Genetics of Colorectal Cancer (PDQ®): Health Professional Version.PDQ Cancer Genetics Editorial Board · 2002PDQ genetics of colorectal cancer summary. Discusses colorectal cancer genetics broadly without mention of specific ATM variants.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. Provides testing algorithms for ataxia genes without discussion of specific ATM variants.Does not name this variant
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PMID 28492532 ↗Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.Nykamp K et al. · 2017Sherloc refinement of ACMG-AMP variant classification criteria. Provides a refined classification framework without discussion of specific ATM variants.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
2 / 1,613,430 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.050
Open source ↗
ClinVar
Captured ClinVar source record
Open source ↗
COSMIC
Captured COSMIC 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/?term=NM_000051.4%3Ac.662%2B13_662…
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/11-108114854-ATC-A?dataset=gn…
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr11-108244127-ATC-A?dataset…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/11-108244127-ATC-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_000051.4%3Ac.662%…
- OncoKB ↗www.oncokb.org/gene/ATM/?
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=ATM+c.662+13_662+14del
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= 1.2396e-06; MAF= 0.00012%, 2/1613430 alleles, homozygotes = 0) and has highest observed frequency in the African/African American population (AF= 1.33558e-05; MAF= 0.00134%, 1/74874 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.05).
Somatic
This variant has not previously been reported in somatic cancers (COSMIC).