0%
ATMc.4997A>CNot classified
Print report
Variant interpretation report

ATM c.4997A>C, p.(Glu1666Ala)

NM_000051.4:c.4997A>C NP_000042.3:p.(Glu1666Ala) View identifiers
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.

About ATM

No gene-level summary was recorded for this case.

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: 2 Benign evidence criteria: 2
Pathogenic criteria applied · 2
PM2Supporting
PM2 · supporting

This variant is present in gnomAD v4.1 at an extremely low frequency (AF=1.86e-06; 3/1,613,480 alleles, 0 homozygotes; grpmax FAF=6.8e-07). Per ATM VCEP v1.5, frequency ≤0.001% in gnomAD v4 qualifies for PM2_Supporting.

PP3Supporting
PP3 · supporting

SpliceAI predicts a possible splicing impact (max delta score = 0.24). Per ATM VCEP v1.5, SpliceAI ≥0.2 qualifies for PP3_Supporting for missense variants via the splicing prediction route. The REVEL score (0.054) does NOT independently support PP3 via the missense pathway (threshold >0.7333).

Benign criteria applied · 2
BS3Moderate
BS3 · moderate

Functional assay data curated by the ATM HBOP VCEP (Suppl_TableS1, based on kinase activity assays: Mitui 2009 PMID 18634022, Barone 2009 PMID 19431188; and radiosensitivity assays: Mitui 2009, Scott 2002 PMID 11805335) classify NM_000051.4:c.4997A>C (p.E1666A) as 'Functional' with High confidence (combined score 0.456). The variant rescues both ATM-specific kinase activity (phosphorylation of ATM targets) and cellular radiosensitivity, satisfying the VCEP BS3_Moderate threshold: variant rescues both an ATM-specific feature AND radiosensitivity.

BP4Supporting
BP4 · supporting

The REVEL score for this variant is 0.054, which is ≤0.249, meeting the ATM VCEP BP4_Supporting threshold for missense variants. Multiple in silico predictors support a benign effect: REVEL 0.054, BayesDel -0.367, EVE 0.058, AlphaMissense 0.1033. The SpliceAI delta (0.24) does NOT support BP4 via the splicing route (threshold ≤0.1).

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, PP3 supporting, BS3 moderate, 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
3 / 1,613,480 alleles

gnomAD v4.1: 3 / 1,613,480 alleles. Recorded AF 1.85934e-06. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.18512e-05; MAF= 0.00319%, 1/31396 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.48172e-05; MAF= 0.00648%, 1/15428 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

Applied · PM2 →
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.240 maximum delta

Recorded SpliceAI maximum delta score: 0.240. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3, BP4 → SpliceAI ↗
ClinVar submissions
5 reported laboratory submissions

4 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.

Applied · BS3 → 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
COSMIC ↗Cancer Hotspots ↗
For specialists

Technical detail

ACMG/AMP criteria under ClinGen ATM VCEP v1.5, with the data and sources behind each one.

26 criteria with recorded statuses: 4 met · 7 not met · 0 not assessed · 15 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM5PM6PP1PP2PP3PP4PP5PS5
Benign
BA1BS1BS2BS3BS4BP1BP2BP4BP5BP6BP7
Met Not met Not assessed Not applicable

NM_000051.4:c.4997A>C (p.Glu1666Ala) is a missense variant at an extremely low population frequency (gnomAD v4.1 AF = 1.86e-06, 3/1,613,480 alleles).

Functional assay data curated by the ClinGen HBOP VCEP demonstrate that p.Glu1666Ala rescues both ATM kinase activity and cellular radiosensitivity to wild-type levels, consistent with a benign functional effect (BS3_Moderate).

Multiple in silico predictors support a benign effect: REVEL 0.054 (≤0.249, BP4_Supporting), BayesDel -0.367, EVE 0.058, AlphaMissense 0.1033.

SpliceAI predicts a possible splicing impact (max delta 0.24, ≥0.2) qualifying for PP3_Supporting under the VCEP splicing prediction rule, though this is modestly above threshold and conflicts with the benign in silico and functional evidence.

The variant is absent from COSMIC and no case-control or segregation studies are available. Six publications provided by ClinVar were reviewed in full text; none mention NM_000051.4:c.4997A>C specifically.

Met · 4

PM2 SupportingThis variant is present in gnomAD v4.1 at an extremely low frequency (AF=1.86e-06; 3/1,613,480 alleles, 0 homozygotes; grpmax FAF=6.8e-07). Per ATM VCEP v1.5, frequency ≤0.001% in gnomAD v4 qualifies for PM2_Supporting. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 AF = 1.86e-06 (0.000186%)
  • ≤0.001% threshold met
  • 3 alleles in 1
  • 613
  • 480
  • no homozygotes.
Sources
gnomad_v4 ↗
PP3 SupportingSpliceAI predicts a possible splicing impact (max delta score = 0.24). Per ATM VCEP v1.5, SpliceAI ≥0.2 qualifies for PP3_Supporting for missense variants via the splicing prediction route. The REVEL score (0.054) does NOT independently support PP3 via the missense pathway (threshold >0.7333). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.24
  • ≥0.2 threshold for splicing prediction met
  • REVEL 0.054 does not meet missense threshold (>0.7333).
Still missing
  • SpliceAI score of 0.24 is modestly above the 0.2 threshold
  • RNA studies would clarify splicing impact.
Sources
spliceai ↗
BS3 ModerateFunctional assay data curated by the ATM HBOP VCEP (Suppl_TableS1, based on kinase activity assays: Mitui 2009 PMID 18634022, Barone 2009 PMID 19431188; and radiosensitivity assays: Mitui 2009, Scott 2002 PMID 11805335) classify NM_000051.4:c.4997A>C (p.E1666A) as 'Functional' with High confidence (combined score 0.456). The variant rescues both ATM-specific kinase activity (phosphorylation of ATM targets) and cellular radiosensitivity, satisfying the VCEP BS3_Moderate threshold: variant rescues both an ATM-specific feature AND radiosensitivity. Details ▾Hide ▴
Evidence considered
  • VCEP functional data: E1666A classified as 'Functional' (High confidence)
  • rescues ATM kinase activity (Mitui 2009
  • Barone 2009) and radiosensitivity (Mitui 2009
  • Scott 2002)
  • approved assays with PS3_supporting/BS3_supporting (kinase) and BS3_Supporting (radiosensitivity) proposed weights.
Sources
vcep_suppl_tables1_pmid_40580951vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1
BP4 SupportingThe REVEL score for this variant is 0.054, which is ≤0.249, meeting the ATM VCEP BP4_Supporting threshold for missense variants. Multiple in silico predictors support a benign effect: REVEL 0.054, BayesDel -0.367, EVE 0.058, AlphaMissense 0.1033. The SpliceAI delta (0.24) does NOT support BP4 via the splicing route (threshold ≤0.1). Details ▾Hide ▴
Evidence considered
  • REVEL = 0.054 (≤0.249)
  • BayesDel = -0.367
  • EVE = 0.058
  • AlphaMissense = 0.1033
  • all in silico predictors support a benign effect.
Sources
revelbayesdelvcep_suppl_tables1_pmid_40580951

Not met · 7 · evaluated, threshold not reached

PS1 PS1 requires a (likely) pathogenic variant at the same nucleotide position with a different nucleotide change. At c.4997, alternative changes c.4997A>T (p.E1666V) and c.4997A>G (p.E1666G) exist but neither is classified as pathogenic or likely pathogenic in ClinVar. No qualifying PS1 comparator is identified. Details ▾Hide ▴
Evidence considered
  • No P/LP variant at c.4997 with a different nucleotide change
  • c.4997A>T and c.4997A>G are not classified as P/LP.
Sources
clinvar ↗vcep_suppl_tables1_pmid_40580951
PS3 PS3 requires experimental evidence of a damaging effect on ATM function. The ATM VCEP functional assay data (Suppl_TableS1, PMIDs 18634022, 19431188, 11805335) classifies c.4997A>C (p.E1666A) as 'Functional' (combined score 0.456, High confidence), indicating the variant retains normal kinase activity and radiosensitivity rescue. No evidence of damaging functional effect exists; the functional data support benign effect (see BS3). Details ▾Hide ▴
Evidence considered
  • VCEP functional data: variant classified as 'Functional' with High confidence
  • rescues both kinase activity and radiosensitivity in published assays (Mitui 2009
  • Barone 2009
  • Scott 2002).
Sources
vcep_suppl_tables1_pmid_40580951vcep_atm_pvs1_1_5
PS4 The ATM VCEP requires case-control studies with p-value ≤0.05 AND (OR/HR/RR ≥2 OR lower 95% CI ≥1.5) for PS4. No such case-control studies have been identified for NM_000051.4:c.4997A>C. The variant is absent from COSMIC and has no enrichment data in affected vs. control populations. Details ▾Hide ▴
Evidence considered
  • No case-control studies identified
  • variant not reported in COSMIC.
Sources
clinvar ↗
PP1 The ATM VCEP applies PP1 only for autosomal recessive (ataxia telangiectasia) conditions, requiring segregation in affected relatives. No segregation data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No segregation data available
  • no family studies identified.
Still missing
  • No family segregation data available.
BA1 The ATM VCEP BA1 threshold is grpmax Filtering AF >0.5% in gnomAD v4. The grpmax FAF for this variant is 6.8e-07 (0.000068%), far below the 0.5% threshold. BA1 is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 grpmax FAF = 6.8e-07 (0.000068%)
  • not >0.5%.
Sources
gnomad_v4 ↗
BS1 The ATM VCEP BS1 threshold is grpmax Filtering AF >0.05% in gnomAD v4. The grpmax FAF for this variant is 6.8e-07 (0.000068%), far below the 0.05% threshold. BS1 is not met. Details ▾Hide ▴
Evidence considered
  • gnomAD v4.1 grpmax FAF = 6.8e-07 (0.000068%)
  • not >0.05%.
Sources
gnomad_v4 ↗
BP2 BP2 requires observation of the variant in trans with a P/LP variant in an unaffected individual (≥18 years, no evidence of A-T) or homozygous in an unaffected individual per the ATM PM3/BP2 table. No such data are available for this variant. Details ▾Hide ▴
Evidence considered
  • No data on trans or homozygous observations in unaffected individuals.
Still missing
  • No co-occurrence data in unaffected individuals.
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is applicable only to null variants (nonsense, frameshift, canonical splice sites, initiation codon, or exon deletions). NM_000051.4:c.4997A>C is a missense variant (p.Glu1666Ala) and does not fall into any PVS1-eligible variant class per the ATM VCEP PVS1 decision tree. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • not a null variant type eligible for PVS1.
Sources
pvs1_variant_assessment
PS2 VCEPThe ATM HBOP VCEP v1.5 specifies PS2 as Not Applicable: informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase. Details ▾Hide ▴
Evidence considered
  • VCEP declares PS2 Not Applicable for ATM.
PM1 VCEPThe ATM HBOP VCEP v1.5 specifies PM1 as Not Applicable: benign and pathogenic variants occur within the same domains and germline mutational hotspots are not well defined for ATM at this time. Details ▾Hide ▴
Evidence considered
  • VCEP declares PM1 Not Applicable for ATM.
PM5 N/AThe ATM VCEP PM5 rule applies only to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047, or to splice variants with PVS1_Strength(RNA). The VCEP explicitly states: 'Do not use for missense changes.' NM_000051.4:c.4997A>C is a missense variant and is not eligible for PM5. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • VCEP PM5 restricted to truncating/splice variants only.
Sources
pm5_candidates
PM6 VCEPThe ATM HBOP VCEP v1.5 specifies PM6 as Not Applicable: informative de novo occurrences have not been observed and de novo AR conditions are unlikely to be informed by phase. Details ▾Hide ▴
Evidence considered
  • VCEP declares PM6 Not Applicable for ATM.
PP2 VCEPThe ATM HBOP VCEP v1.5 specifies PP2 as Not Applicable: ATM does not have a defined low rate of missense benign variation. Details ▾Hide ▴
Evidence considered
  • VCEP declares PP2 Not Applicable for ATM.
PP4 VCEPThe ATM HBOP VCEP v1.5 specifies PP4 as Not Applicable: breast cancer has multiple genetic etiologies (genetic heterogeneity) and no features readily distinguish hereditary from sporadic causes; for ataxia telangiectasia, such evidence is built into the PM3/BP2 table. Details ▾Hide ▴
Evidence considered
  • VCEP declares PP4 Not Applicable for ATM.
PP5 VCEPThe ATM HBOP VCEP v1.5 specifies PP5 as Not Applicable for this VCEP, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Evidence considered
  • VCEP declares PP5 Not Applicable for this VCEP.
BS2 VCEPThe ATM HBOP VCEP v1.5 specifies BS2 as Not Applicable: ATM has incomplete penetrance. Details ▾Hide ▴
Evidence considered
  • VCEP declares BS2 Not Applicable for ATM.
BS4 VCEPThe ATM HBOP VCEP v1.5 specifies BS4 as Not Applicable: co-segregation analysis in low-penetrance genes can produce false positives; informative instances of lack of co-segregation in A-T families are too rare to be considered. Details ▾Hide ▴
Evidence considered
  • VCEP declares BS4 Not Applicable for ATM.
BP1 VCEPThe ATM HBOP VCEP v1.5 specifies BP1 as Not Applicable: missense pathogenic variants are known for ATM. Details ▾Hide ▴
Evidence considered
  • VCEP declares BP1 Not Applicable for ATM.
BP5 VCEPThe ATM HBOP VCEP v1.5 specifies BP5 as Not Applicable: cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype, and ATM has low penetrance with higher tolerance in the general population. Details ▾Hide ▴
Evidence considered
  • VCEP declares BP5 Not Applicable for ATM.
BP6 VCEPThe ATM HBOP VCEP v1.5 specifies BP6 as Not Applicable for this VCEP, per ClinGen Sequence Variant Interpretation VCEP Review Committee recommendation. Details ▾Hide ▴
Evidence considered
  • VCEP declares BP6 Not Applicable for this VCEP.
BP7 N/ABP7 per the ATM VCEP applies to synonymous variants and deep intronic variants (beyond +7 donor / -21 acceptor). NM_000051.4:c.4997A>C is a missense variant, not synonymous. BP7(RNA) requires observed lack of aberrant RNA splicing defect, which has not been assessed for this variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 restricted to synonymous and deep intronic variants per VCEP. No RNA splicing data available.
PS5 N/APS5 is not a standard ACMG/AMP criterion. No VCEP or generic ACMG rule exists for this code. Details ▾Hide ▴
Evidence considered
  • Not a recognized ACMG/AMP criterion.

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.4997A>C
Protein (HGVS p.)
NP_000042.3:p.(Glu1666Ala)
GRCh38
chr11:108297374 A>C
GRCh37
chr11:108168101 A>C
ClinVar
1043495

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…
gnomAD v4.1 3 / 1,613,480 alleles AF 1.86e-06 · 0 homozygotes · FAF 6.8e-07
gnomAD v2.1 1 / 31,396 alleles AF 3.19e-05 · 0 homozygotes
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 1.9e-06 · 3 / 1,613,480 alleles · 0 hom · FAF 6.8e-07
European (non-Finnish)3 / 1,179,586 2.5e-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.

gnomAD v2.1

AF 3.2e-05 · 1 / 31,396 alleles · 0 hom
European (non-Finnish)1 / 15,428 6.5e-05
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

This variant is present in gnomAD v4.1 (AF= 1.85934e-06; MAF= 0.00019%, 3/1613480 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54327e-06; MAF= 0.00025%, 3/1179586 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.18512e-05; MAF= 0.00319%, 1/31396 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.48172e-05; MAF= 0.00648%, 1/15428 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -87 bp
0.240
SpliceAI acceptor gainat +3 bp
0.000
SpliceAI donor lossat +8 bp
0.200
SpliceAI donor gainat +7 bp
0.000
Pangolin splice lossmagnitude shown
-0.240
Pangolin splice gain
0.000

Other predictors

REVEL
0.054
BayesDel
-0.367

How the predictions were used

PP3 SupportingSpliceAI predicts a possible splicing impact (max delta score = 0.24). Per ATM VCEP v1.5, SpliceAI ≥0.2 qualifies for PP3_Supporting for missense variants via the splicing prediction route. The REVEL score (0.054) does NOT independently support PP3 via the missense pathway (threshold >0.7333). Details ▾Hide ▴
Evidence considered
  • SpliceAI max delta = 0.24
  • ≥0.2 threshold for splicing prediction met
  • REVEL 0.054 does not meet missense threshold (>0.7333).
Still missing
  • SpliceAI score of 0.24 is modestly above the 0.2 threshold
  • RNA studies would clarify splicing impact.
Sources
spliceai ↗
BP4 SupportingThe REVEL score for this variant is 0.054, which is ≤0.249, meeting the ATM VCEP BP4_Supporting threshold for missense variants. Multiple in silico predictors support a benign effect: REVEL 0.054, BayesDel -0.367, EVE 0.058, AlphaMissense 0.1033. The SpliceAI delta (0.24) does NOT support BP4 via the splicing route (threshold ≤0.1). Details ▾Hide ▴
Evidence considered
  • REVEL = 0.054 (≤0.249)
  • BayesDel = -0.367
  • EVE = 0.058
  • AlphaMissense = 0.1033
  • all in silico predictors support a benign effect.
Sources
revelbayesdelvcep_suppl_tables1_pmid_40580951
BP7 N/ABP7 per the ATM VCEP applies to synonymous variants and deep intronic variants (beyond +7 donor / -21 acceptor). NM_000051.4:c.4997A>C is a missense variant, not synonymous. BP7(RNA) requires observed lack of aberrant RNA splicing defect, which has not been assessed for this variant. Details ▾Hide ▴
Evidence considered
  • Missense variant
  • BP7 restricted to synonymous and deep intronic variants per VCEP. No RNA splicing data available.

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.24). REVEL score = 0.054. BayesDel score = -0.367169.

6 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

  • 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.
    Standards and guidelines for the interpretation of sequence variants by ACMG/AMP. Provides the generic ACMG/AMP classification framework but does not discuss any specific ATM variants.
    Does not name this variant
    PMID 25741868 ↗
  • Genetic cancer risk assessment and counseling: recommendations of the national society of genetic counselors.
    Trepanier A et al. · 2004
    NSGC practice recommendations for genetic cancer risk assessment and counseling. Provides general guidance on hereditary cancer syndromes but does not discuss any specific ATM variants.
    Does not name this variant
    PMID 15604628 ↗
  • Risk assessment and genetic counseling for hereditary breast and ovarian cancer: recommendations of the National Society of Genetic Counselors.
    Berliner JL et al. · 2007
    NSGC recommendations for risk assessment and genetic counseling for hereditary breast and ovarian cancer. Discusses BRCA1/BRCA2 testing guidelines but does not discuss any specific ATM variants.
    Does not name this variant
    PMID 17508274 ↗
  • The emerging landscape of breast cancer susceptibility.
    Stratton MR et al. · 2008
    Review of breast cancer susceptibility genes including ATM as a moderate-penetrance gene. Discusses ATM at the gene level as a breast cancer risk gene but does not mention any specific ATM variant.
    Does not name this variant
    PMID 18163131 ↗
  • Risk assessment, genetic counseling, and genetic testing for BRCA-related cancer in women: U.S. Preventive Services Task Force recommendation statement.
    Moyer VA et al. · 2014
    USPSTF recommendation statement on BRCA-related cancer risk assessment and genetic testing. Focuses on BRCA1/BRCA2 screening recommendations; does not discuss ATM or any specific ATM variants.
    Does not name this variant
    PMID 24366376 ↗
  • 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. · 2015
    ACMG/NSGC practice guideline for referral indications for cancer predisposition assessment. Lists referral criteria for various hereditary cancer syndromes but does not discuss any specific ATM variants.
    Does not name this variant
    PMID 25394175 ↗

Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.

gnomAD v4.1 3 / 1,613,480 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.240 Open source ↗
ClinVar 4 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

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= 1.85934e-06; MAF= 0.00019%, 3/1613480 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 2.54327e-06; MAF= 0.00025%, 3/1179586 alleles, homozygotes = 0); grpmax FAF= 6.8e-07.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.18512e-05; MAF= 0.00319%, 1/31396 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.48172e-05; MAF= 0.00648%, 1/15428 alleles, homozygotes = 0).

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (4 clinical laboratories) and as Likely benign (1 clinical laboratory). (ClinVarID = 1043495)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.24). REVEL score = 0.054. BayesDel score = -0.367169.

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.