0%
ATMc.3802delPathogenic
Print report
Variant interpretation report

ATM c.3802del, p.Val1268Ter

NM_000051.4:c.3802del NP_000042.3:p.(Val1268Ter) Nonsense · exon 26 View identifiers
Classification
Pathogenic

Variant description:

The ATM NM_000051.4:c.3802del (NP_000042.3:p.(Val1268Ter)) nonsense variant has previously been reported in somatic cancers (COSMIC; COSV53739410, n = 4 times). This variant is predicted to result in an absent or disrupted protein product. Based on available guidelines, this variant is considered to be Pathogenic. This variant is considered to be Pathogenic by the VCEP (ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen; ClinVar ID 127374).

Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.

Pathogenic.A pathogenic classification under the recorded framework.

In plain language

Gene-level background from the recorded interpretation.

About ATM

ATM encodes a kinase that acts as a master controller of the cellular DNA damage response: it detects double-strand breaks and coordinates DNA repair, cell cycle arrest, or apoptosis through downstream targets including p53, BRCA1, and CHK2. Loss-of-function mutations in both copies of ATM cause ataxia telangiectasia, an autosomal recessive disorder characterized by neurological problems, immune deficiency, and cancer predisposition. ATM functions as a tumor suppressor: individuals with ataxia telangiectasia are prone to childhood lymphomas, leukemias, and breast cancer, while carriers of a single altered copy have increased risk of breast, pancreatic, prostate, and other cancers. Somatic ATM mutations also occur in lymphoid malignancies and solid tumors, and ATM-deficient cancers are often especially sensitive to DNA-damaging treatments.

NCBI Gene ↗ OncoKB ↗
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 v1.6. 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: 4 Benign evidence criteria: 0
Pathogenic criteria applied · 4
PVS1Very strong
PVS1 · very strong

Met, full-strength PVS1: p.Val1268Ter is a nonsense termination far upstream of the VCEP NMD boundary at p.Glu2979 in ATM, whose loss of function causes disease.

PM3Moderate
PM3 · moderate

Met at Moderate: one unrelated classical A-T proband was homozygous for 3802delG, providing the VCEP table's 2.0 PM3 points.

PM5Supporting
PM5 · supporting

Met, Supporting: p.Val1268Ter is a truncating ATM allele upstream of p.Leu3048, satisfying the VCEP's DNA PM5 cutoff when PVS1 is VeryStrong.

PP5Supporting
PP5 · supporting

Not applicable: the VCEP explicitly prohibits PP5 use under its governing ATM specification.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Pathogenic

Pathogenic: ATM VCEP Rule4 is satisfied by PVS1 very strong plus at least two supporting-strength criteria, including PM3 moderate, PM5 supporting, and PP5 supporting.

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
135 / 1,613,134 alleles

gnomAD v4.1: 135 / 1,613,134 alleles. Recorded AF 8.3688e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.89323e-05; MAF= 0.00389%, 11/282542 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.47314e-05; MAF= 0.00847%, 3/35406 alleles, homozygotes = 0); grpmax FAF= 2.858e-05.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
SpliceAI score
0.045 maximum delta

Recorded SpliceAI maximum delta score: 0.045. Refer to the recorded PP3/BP4 rationale for interpretation.

No listed criterion applied SpliceAI ↗
ClinVar submissions
41 reported laboratory submissions

39 Pathogenic · 1 Likely pathogenic · 1 pathogenic. ClinVar API review status: reviewed by expert panel.

Applied · PP5 → ClinVar ↗
Functional evidence
Statement recorded

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

No listed criterion applied OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
4 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV53739410, n = 4 times).

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 v1.6, with the data and sources behind each one.

28 criteria with recorded statuses: 4 met · 4 not met · 4 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.

Pathogenic
PVS1PS1PS2PS3PS4PM1PM2PM3PM4PM5PM6PP1PP2PP3PP4PP5
Benign
BA1BS1BS2BS3BS4BP1BP2BP3BP4BP5BP6BP7
Met Not met Not assessed Not applicable

PVS1 is met at very strong strength under the ATM VCEP because c.3802del creates p.Val1268Ter in an NMD-prone position, while PM4 and BP3 are not applicable under their VCEP rules.

Among the requested codon, residue, and domain criteria, only PM5 applies: the ATM VCEP assigns PM5_Supporting to qualifying NMD-prone truncating DNA variants upstream of p.Leu3048.

PS1, PM1, PP2, and BP1 are not applicable under the ATM VCEP's explicit variant-type or criterion-use instructions.

PS2, PM6, and BS4 are excluded by the ATM VCEP's explicit not-applicable designations.

PP1 remains unassessed because the available reports do not document segregation in affected relatives or informative meioses.

Within the requested criteria only, PS4 is not met because the exact-variant case-control comparison fails the VCEP's required p-value and lower-confidence-bound conditions; PP4, PP5, BP5, and BP6 are VCEP-defined not applicable criteria.

All three requested computational-evidence criteria are upstream not_applicable because the variant is a truncating coding deletion outside their governing variant-type scopes; no PP3, BP4, or BP7 code is assigned.

Met · 4

PVS1 Very strongVCEPMet, full-strength PVS1: p.Val1268Ter is a nonsense termination far upstream of the VCEP NMD boundary at p.Glu2979 in ATM, whose loss of function causes disease. Details ▾Hide ▴
Reasoning

NM_000051.4:c.3802del is a one-base deletion producing the nonsense consequence NP_000042.3:p.(Val1268Ter) / p.(V1268*) in coding exon 26. The ATM VCEP treats nonsense variants predicted to undergo NMD as full-strength PVS1, and this termination occurs at p.Val1268, well upstream of the VCEP's NMD boundary at p.Glu2979; the transcript is the VCEP-relevant ATM RefSeq transcript and ATM loss of function is an established disease mechanism in the governing framework. The VCEP PVS1 file contains no variant-specific pre-assigned row for c.3802del, p.Val1268Ter, or p.V1268*, so the applicable decision-tree rule was applied rather than a table assignment. Published exact-variant observations report 3802delG as a truncated/prematurely truncated ATM protein in patients with ataxia-telangiectasia and in a familial breast-cancer case.

VCEP rule
Nonsense or frameshift | Predicted to undergo NMD (p.Ser2_Glu2979) | PVS1
Evidence considered
  • Variant assessment: NM_000051.4:c.3802del; NP_000042.3:p.(Val1268Ter) / p.(V1268*); nonsense consequence in exon 26.
  • ATM_PVS1_1.6.pdf decision-tree rule applied: Nonsense or frameshift predicted to undergo NMD (p.Ser2_Glu2979) receives PVS1.
  • The termination at p.Val1268 is upstream of the VCEP's stated NMD-predicted interval endpoint p.Glu2979 and is not an extreme 3' ATM variant.
  • ATM_PVS1_1.6.pdf.txt was searched for c.3802del, p.Val1268Ter, and p.V1268*; no variant-specific pre-assigned row was found.
  • PMID:17124347, Table 3, exon 28: 3802delG is reported in AT42RM and AT105RM as a deletion producing a truncated protein.
  • PMID:16832357, Table 1, Family 4: 3802delG is reported as a premature truncation.
Still missing
  • No variant-specific pre-assigned entry for c.3802del, p.Val1268Ter, or p.V1268* was found in ATM_PVS1_1.6.pdf.txt after searching all three notations.
Sources
vcep_atm_pvs1_1_6 ↗cspec ↗pvs1_variant_assessmentPMID:17124347 ↗PMID:16832357 ↗
PM3 ModerateVCEPMet at Moderate: one unrelated classical A-T proband was homozygous for 3802delG, providing the VCEP table's 2.0 PM3 points. Details ▾Hide ▴
Reasoning

The ATM VCEP PM3/BP2 table assigns 2.0 PM3 points for one unrelated A-T proband with a confident phenotype and a homozygous variant. PMID:17124347 reports the exact allele as 3802delG in AT105RM, a homozygous patient with classical ataxia-telangiectasia, yielding 2.0 points and PM3_Moderate. The same paper reports AT42RM as heterozygous for 3802delG and 3576G>A, but does not establish phase sufficiently for an additional PM3 allocation. The governing VCEP file was searched for c.3802del, p.Val1268Ter, and p.V1268*; no variant-specific pre-assigned row was found.

VCEP rule
PM3 = **2** points See ATM PM3/BP2 table for approach to assign points per proband.
Evidence considered
  • ATM PM3/BP2 table, Points per unrelated A-T Proband (PM3), Homozygous and Phenotype confident row: 2.0 points.
  • ATM PM3/BP2 table, strength conversion: 2.0 PM3 points corresponds to Moderate.
  • Table 3, exon 28, PMID:17124347: AT105RM (hom), 3802delG, deletion/truncated protein; the study cohort comprised patients with classical ataxia-telangiectasia.
  • Table 3, exon 28, PMID:17124347: AT42RM (het), 3802delG, with 3576G>A also listed for AT42RM; phase was not established in the consulted evidence.
Still missing
  • ATM_PM3_BP2_1.6.pdf was searched for c.3802del, p.Val1268Ter, and p.V1268*; no variant-specific pre-assigned row was found.
  • For AT42RM, the phase between 3802delG and 3576G>A is not established in the available evidence, so no additional phase-based PM3 points were assigned.
Sources
vcep_atm_pm3_bp2_1_6 ↗PMID:17124347 ↗
PM5 SupportingVCEPMet, Supporting: p.Val1268Ter is a truncating ATM allele upstream of p.Leu3048, satisfying the VCEP's DNA PM5 cutoff when PVS1 is VeryStrong. Details ▾Hide ▴
Reasoning

The ATM VCEP defines PM5_Supporting for DNA variants that are NMD-prone truncating variants receiving PVS1 at VeryStrong, with a premature termination codon upstream of p.Leu3048. This variant is a truncating nonsense allele at p.Val1268Ter, far upstream of p.Leu3048, and the ATM VCEP identifies loss of function as an established disease mechanism; the available case evidence reports the same allele as 3802delG with a truncated/prematurely truncated protein in affected individuals. Therefore the VCEP PM5 DNA rule is met at Supporting strength.

VCEP rule
DNA Variants: Apply to all NMD-prone, truncating variants receiving PVS1 (must be at VeryStrong) with premature termination codons upstream of p.Leu3048
Evidence considered
  • ATM CSPEC PM5 DNA rule: apply PM5 to NMD-prone truncating variants receiving PVS1 at VeryStrong with premature termination codons upstream of p.Leu3048; this variant is p.Val1268Ter.
  • pvs1_gene_context.json records the official ATM CSPEC/VCEP loss-of-function mechanism as supported and the PVS1 gene gate as eligible.
  • DHPLC screening paper, Table 3, exon 28: 3802delG was reported in AT42RM and AT105RM as a deletion producing a truncated protein.
  • Renwick et al. 2006, Table 1 Family 4: 3802delG was listed as a premature truncation and reported previously in ataxia-telangiectasia families.
Sources
cspec ↗pvs1_gene_contextPMID:17124347 ↗PMID:16832357 ↗
PP5 SupportingVCEPNot applicable: the VCEP explicitly prohibits PP5 use under its governing ATM specification. Details ▾Hide ▴
Reasoning

Expert panel ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen classified as Pathogenic.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 PP5 instructions: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
  • ClinVar expert panel classification
Sources
cspec ↗clinvar ↗

Not met · 4 · evaluated, threshold not reached

PS4 VCEPNot met: one case versus zero controls yielded corrected OR 3.54 (95% CI 0.144-87.0) and Fisher p=1.00, failing the VCEP p<=.05 and lower-CI>=1.5 requirements. Details ▾Hide ▴
Reasoning

The VCEP PS4 rule requires a case-control study with p-value <=.05 and either an odds ratio, hazard ratio, or relative risk >=2 or a lower 95% CI >=1.5. Renwick et al. directly reports ATM 3802delG in 1 of 443 familial breast-cancer cases and 0 of 521 controls, so this is a case-control comparison. Using a Haldane-Anscombe correction for the zero control cell, the OR is 3.54 with 95% CI 0.144-87.0; the two-sided Fisher exact p-value is 1.00. The required inequalities are OR 3.54 >= 2? yes, lower 95% CI 0.144 >= 1.5? no, and p-value 1.00 <= .05? no. The VCEP PS4 requirements are therefore not met. The other reviewed variant-specific paper reports affected A-T patients but no unaffected/control comparison.

VCEP rule
Case-control studies; p-value ≤.05 **and** (Odds ratio, hazard ratio, or relative risk ≥2 **or** lower 95% CI ≥1.5).
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 PS4 rule: case-control studies require p-value <=.05 and (odds ratio, hazard ratio, or relative risk >=2 or lower 95% CI >=1.5).
  • Renwick et al. 2006, Table 1, Family 4: ATM 3802delG occurred in 1 of 443 familial breast-cancer cases and 0 of 521 controls; this exact-variant case-control count was analyzed directly.
  • For the zero control cell, a Haldane-Anscombe 0.5 correction was used: OR=(1.5 x 521.5)/(442.5 x 0.5)=3.53559; Wald 95% CI=0.143662-87.0127. The two-sided Fisher exact p-value for the 1/443 versus 0/521 comparison is 1.00.
  • Magliozzi et al. 2006, Table 3, reports 3802delG in two classical ataxia-telangiectasia patients (one heterozygous and one homozygous), but provides no unaffected/control comparison for this variant.
Sources
cspec ↗PMID:16832357 ↗PMID:17124347 ↗
PM2 VCEPNot met: the highest all-comers gnomAD v4.1 subpopulation AF is 0.01119%, exceeding the VCEP PM2 threshold of ≤0.001%. Details ▾Hide ▴
Reasoning

The ATM VCEP PM2 rule assigns PM2_Supporting only when the frequency is at most 0.001% in the gnomAD subpopulation with the highest frequency. In all-comers gnomAD v4.1, the highest subpopulation frequency is 0.000111934 (0.01119%) in European non-Finnish individuals, which exceeds 0.001%; the gnomAD v2.1 highest subpopulation frequency likewise exceeds the threshold at 0.0000847314 (0.00847%). The VCEP does not specify a non-cancer or exome-only source for PM2, so the default all-comers gnomAD entries apply.

VCEP rule
Frequency ≤.001% in gnomAD subpopulation with the highest frequency
Evidence considered
  • ClinGen ATM VCEP CSPEC PM2 entry: "Frequency ≤.001% in gnomAD subpopulation with the highest frequency" and the stated single-observation exception; the exception is not needed here.
  • gnomAD v4.1 all-comers: highest subpopulation was European (non-Finnish), AF=0.000111934 (0.01119%), 132/1,179,266 alleles, homozygotes=0; this exceeds 0.001%.
  • gnomAD v2.1 all-comers: highest subpopulation was Admixed American, AF=8.47314e-05 (0.00847%), 3/35,406 alleles, homozygotes=0; this also exceeds 0.001%.
  • The governing VCEP text does not specify a non-cancer or exome-only population source for PM2; therefore the default all-comers gnomAD entries were used.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BA1 VCEPNot met: gnomAD v4.1 grpmax filtering AF is 0.009614%, below the VCEP BA1 threshold of >0.5%. Details ▾Hide ▴
Reasoning

The ATM VCEP BA1 rule is met only when the gnomAD group maximum filtering allele frequency exceeds 0.5%. The all-comers gnomAD v4.1 group maximum filtering allele frequency is 9.614e-05 (0.009614%), based on the highest population frequency of 0.000111934 (0.01119% in European non-Finnish individuals), which is below 0.5%. The VCEP does not require a non-cancer or exome-only source for BA1, so the default all-comers gnomAD value applies.

VCEP rule
Grpmax Filtering AF >.5% in gnomAD
Evidence considered
  • ClinGen ATM VCEP CSPEC BA1 entry: "Grpmax Filtering AF >.5% in gnomAD".
  • gnomAD v4.1 all-comers: grpmax FAF=9.614e-05 (0.009614%); highest population was European (non-Finnish), AF=0.000111934 (0.01119%), 132/1,179,266 alleles, homozygotes=0.
  • The governing VCEP text does not specify a non-cancer or exome-only population source for BA1; therefore the default all-comers gnomAD entry was used.
Sources
cspec ↗gnomad_v4 ↗
BS1 VCEPNot met: gnomAD v4.1 grpmax filtering AF is 0.009614%, below the VCEP BS1 threshold of >0.05%. Details ▾Hide ▴
Reasoning

The ATM VCEP BS1 rule is met only when the gnomAD group maximum filtering allele frequency exceeds 0.05%. The all-comers gnomAD v4.1 group maximum filtering allele frequency is 9.614e-05 (0.009614%), below 0.05%. The VCEP does not require a non-cancer or exome-only source for BS1, so the default all-comers gnomAD value applies.

VCEP rule
Grpmax Filtering AF >.05% in gnomAD
Evidence considered
  • ClinGen ATM VCEP CSPEC BS1 entry: "Grpmax Filtering AF >.05% in gnomAD".
  • gnomAD v4.1 all-comers: grpmax FAF=9.614e-05 (0.009614%); highest population was European (non-Finnish), AF=0.000111934 (0.01119%), 132/1,179,266 alleles, homozygotes=0.
  • The governing VCEP text does not specify a non-cancer or exome-only population source for BS1; therefore the default all-comers gnomAD entry was used.
Sources
cspec ↗gnomad_v4 ↗

Not assessed · 4 · no assessment recorded

PS3 VCEPNot assessed: variant-specific reports identify a truncating allele but provide no ATM-specific functional assay readout required by the VCEP. Details ▾Hide ▴
Reasoning

The ATM VCEP requires variant-specific functional evidence showing failure to rescue an ATM-specific feature for PS3_Supporting, or failure to rescue both an ATM-specific feature and radiosensitivity for PS3_Moderate. The approved-assay supplementary file is a methodology and strength-calibration table, not a per-variant results table, and searches for c.3802del, p.Val1268Ter, and p.V1268* found no entry. Sun et al. 2025 Supplementary Table S1 likewise contains no exact c.3802del row; the nearby c.3802G>A/C/T SNV rows are different variants. PMID:17124347 and PMID:16832357 report 3802delG as a truncating allele, but provide no approved ATM-specific assay readout for this allele. Therefore PS3 cannot be assessed from the available variant-specific functional evidence.

VCEP rule
Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 PS3 rule: PS3_Supporting requires failure to rescue an ATM-specific feature, while PS3_Moderate requires failure to rescue both an ATM-specific feature and radiosensitivity; PS3 is not used as strong.
  • clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx, sheets 'ATM kinase activity' and 'ATM radiosensitivity': approved assay methodology and proposed strength calibration, but no row for c.3802del, p.Val1268Ter, or p.V1268*.
  • Sun et al. 2025 Supplementary Table S1, searched by cHGVS/protein notation: no exact c.3802del/p.Val1268Ter/p.V1268* row; nearby c.3802G>A, c.3802G>C, and c.3802G>T entries are distinct SNVs and cannot be used for this deletion.
  • DHPLC screening of ATM in Italian ataxia-telangiectasia patients, PMID:17124347, Table 3: 3802delG is listed in exon 28 in heterozygous and homozygous patients as a deletion producing a truncated protein, without a variant-specific ATM functional assay readout.
  • ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles, PMID:16832357, Table 1: 3802delG is listed as a premature truncation in one familial breast cancer case, without a variant-specific ATM functional assay readout.
Still missing
  • No c.3802del, p.Val1268Ter, or p.V1268* entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx.txt.
  • No c.3802del, p.Val1268Ter, or p.V1268* entry was found in Suppl_TableS1_PMID 40580951.xlsx.txt; the file contains only different c.3802 SNV rows.
  • A variant-specific approved ATM kinase-activity result, with or without qualifying radiosensitivity data, is not available in the reviewed evidence.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:17124347 ↗PMID:16832357 ↗
PP1 VCEPNot assessed: reports identify affected carriers, but document no segregation in an affected relative, the VCEP's minimum PP1 evidence threshold. Details ▾Hide ▴
Reasoning

The ATM VCEP applies PP1 for autosomal-recessive disease when the variant segregates in affected relatives: supporting for 1, moderate for 2, and strong for at least 3 affected relatives. The available variant-specific reports identify 3802delG in affected A-T patients and in one familial breast-cancer case, but they do not document segregation of this variant in affected relatives, parental transmission, or a count of informative meioses. Therefore no PP1 strength can be assigned.

VCEP rule
AR Condition: Segregation in ≥3 affected relatives ... AR Condition: Segregation in 2 affected relatives ... AR Condition: Segregation in 1 affected relative
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 PP1 rule: "AR Condition: Segregation in 1 affected relative" is supporting, "AR Condition: Segregation in 2 affected relatives" is moderate, and "AR Condition: Segregation in ≥3 affected relatives" is strong.
  • PMID:17124347, Table 3, exon 28: 3802delG was reported in two classical ataxia-telangiectasia patients, AT42RM (heterozygous) and AT105RM (homozygous); the extracted report does not provide familial segregation data.
  • PMID:16832357, Table 1, Family 4: 3802delG was identified in one familial breast-cancer case; the paper reports no variant-specific segregation result beyond that observation.
Still missing
  • Variant-specific testing results for affected relatives and parents are not reported.
  • The number of informative meioses and any non-segregating affected relatives are not available.
Sources
cspec ↗PMID:17124347 ↗PMID:16832357 ↗
BS3 VCEPNot assessed: variant-specific reports identify a truncating allele but provide no qualifying rescue assay required by the VCEP. Details ▾Hide ▴
Reasoning

The ATM VCEP requires variant-specific functional evidence showing rescue of either an ATM-specific feature or radiosensitivity for BS3_Supporting, and rescue of both for BS3_Moderate. The approved-assay supplementary file is a methodology and strength-calibration table, not a per-variant results table, and searches for c.3802del, p.Val1268Ter, and p.V1268* found no entry. Sun et al. 2025 Supplementary Table S1 contains no exact c.3802del row; its c.3802G>A/C/T rows are different SNVs. PMID:17124347 and PMID:16832357 report 3802delG as a truncating allele but do not report a qualifying rescue assay. Therefore BS3 cannot be assessed from the available variant-specific functional evidence.

VCEP rule
Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 BS3 rule: BS3_Supporting requires rescue of either an ATM-specific feature or radiosensitivity, while BS3_Moderate requires rescue of both.
  • clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx, sheets 'ATM kinase activity' and 'ATM radiosensitivity': approved assay methodology and proposed strength calibration, but no row for c.3802del, p.Val1268Ter, or p.V1268*.
  • Sun et al. 2025 Supplementary Table S1, searched by cHGVS/protein notation: no exact c.3802del/p.Val1268Ter/p.V1268* row; nearby c.3802G>A, c.3802G>C, and c.3802G>T entries are distinct SNVs and cannot be used for this deletion.
  • DHPLC screening of ATM in Italian ataxia-telangiectasia patients, PMID:17124347, Table 3: 3802delG is listed in exon 28 in heterozygous and homozygous patients as a deletion producing a truncated protein, without a variant-specific rescue assay.
  • ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles, PMID:16832357, Table 1: 3802delG is listed as a premature truncation in one familial breast cancer case, without a variant-specific rescue assay.
Still missing
  • No c.3802del, p.Val1268Ter, or p.V1268* entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx.txt.
  • No c.3802del, p.Val1268Ter, or p.V1268* entry was found in Suppl_TableS1_PMID 40580951.xlsx.txt; the file contains only different c.3802 SNV rows.
  • A variant-specific approved ATM kinase-activity or radiosensitivity rescue result is not available in the reviewed evidence.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:17124347 ↗PMID:16832357 ↗
BP2 VCEPNot assessed: no qualifying unaffected-adult cis or trans observation with a pathogenic variant is documented for BP2. Details ▾Hide ▴
Reasoning

The ATM VCEP BP2 rule requires observation in trans with a pathogenic variant for a fully penetrant dominant disorder or in cis with a pathogenic variant in any inheritance pattern, with the table assigning points according to confirmed phase, phase unknown, or homozygosity in an unaffected adult. The available exact-variant evidence reports affected A-T patients and a familial breast-cancer case, but does not document an unaffected adult with a qualifying cis or trans pathogenic-variant observation. The governing VCEP file was searched for c.3802del, p.Val1268Ter, and p.V1268*; no variant-specific pre-assigned row was found.

VCEP rule
BP2 = **\-1** point See ATM PM3/BP2 table for approach to assign points per proband.
Evidence considered
  • ATM PM3/BP2 table, Points per Unaffected (non-A-T) Adult (>18yo) Proband (BP2), requires a qualifying unaffected-adult observation with confirmed trans, phase unknown, or homozygous status.
  • Available exact-variant literature evidence reports affected A-T patients; it does not document an unaffected adult with a qualifying cis or trans pathogenic-variant observation.
Still missing
  • ATM_PM3_BP2_1.6.pdf was searched for c.3802del, p.Val1268Ter, and p.V1268*; no variant-specific pre-assigned row was found.
  • The available evidence does not establish a qualifying unaffected adult, cis phase, or trans phase observation for BP2.
Sources
vcep_atm_pm3_bp2_1_6 ↗
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PS1 N/ANot applicable: PS1 is limited to missense or specified splice-region comparisons, whereas c.3802del is a nonsense variant producing p.Val1268Ter. Details ▾Hide ▴
Reasoning

The variant is a nonsense/truncating change, NP_000042.3:p.(Val1268Ter), not a missense change. The ATM PS1 guide limits the protein-level route to missense changes and directs splice-region cases to its splicing table; this variant is not a splice-region variant. A search of ATM_PS1_1.6.pdf.txt for c.3802del, p.Val1268Ter, and p.V1268* found no variant-specific table entry.

VCEP rule
Use for missense changes as long as splicing is ruled-out for both alterations.  * Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.
Evidence considered
  • Case normalization identifies NM_000051.4:c.3802del as NP_000042.3:p.(Val1268Ter), a nonsense consequence.
  • ATM_PS1_1.6.pdf.txt was searched for c.3802del, p.Val1268Ter, and p.V1268*; no matching variant-specific entry was found.
Still missing
  • No entry for c.3802del, p.Val1268Ter, or p.V1268* was found in ATM_PS1_1.6.pdf.txt; the variant is outside the guide's applicable protein-level variant type.
Sources
cspec ↗vcep_atm_ps1_1_6 ↗
PS2 VCEPNot applicable: the ATM VCEP explicitly designates PS2 as not applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP specification explicitly marks PS2 as not applicable. No de novo evidence can be used for this criterion under the governing VCEP framework.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC criteria entry for PS2: applicability is "Not Applicable".
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP prohibits PM1 because benign and pathogenic variants occur in the same domains and germline hotspots are not well defined. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly instructs that PM1 is not used because benign and pathogenic variants occur within the same domains and germline mutational hotspots are not well defined. The case vcep_materials.json domain_tables object is empty, so there is no approved ATM domain-table entry to evaluate for residue 1268; the VCEP-level prohibition controls.

VCEP rule
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
Evidence considered
  • ATM CSPEC PM1 instructions state: Do not use because benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined.
  • vcep_materials.json domain_tables is empty; no approved ATM domain-table entry was available for residue 1268.
Sources
cspec ↗
PM4 N/ANot applicable: PM4 is restricted to stop-loss variants, whereas c.3802del creates a premature stop at p.Val1268Ter. Details ▾Hide ▴
Reasoning

The ATM VCEP limits PM4 to stop-loss variants. This variant is a one-base deletion producing a premature termination at p.Val1268Ter, not a stop-loss alteration, so PM4 is not applicable.

VCEP rule
Use for stop-loss variants.
Evidence considered
  • The normalized consequence is a premature termination, NP_000042.3:p.(Val1268Ter), rather than loss of an existing stop codon.
Sources
cspec ↗
PM6 VCEPNot applicable: the ATM VCEP explicitly designates PM6 as not applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP specification explicitly marks PM6 as not applicable. The criterion cannot be applied under this VCEP framework, regardless of whether de novo observations are available.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC criteria entry for PM6: applicability is "Not Applicable".
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP does not use PP2, and c.3802del is a nonsense rather than missense variant. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP2 not applicable and instructs not to use it because ATM does not have a defined low rate of benign missense variation. The current variant is also a nonsense/truncating change rather than a missense change.

VCEP rule
Do not use: ATM does not have a defined low rate of missense benign variation.
Evidence considered
  • ATM CSPEC PP2 instructions state: Do not use because ATM does not have a defined low rate of missense benign variation.
  • Case normalization identifies the consequence as p.(Val1268Ter), a nonsense variant.
Sources
cspec ↗
PP3 N/ANot applicable: PP3's ATM splicing path covers silent, missense/in-frame, and qualifying intronic variants, not this truncating c.3802del variant. Details ▾Hide ▴
Reasoning

The variant is a truncating deletion, annotated as ATM c.3802del with p.(Val1268Ter)/p.(V1268*). The ATM VCEP PP3 rule limits its splicing path to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites; this frameshift/nonsense variant is outside that scope. The available SpliceAI max delta of 0.045 is therefore not used for PP3. The governing full-text file Suppl_TableS1_PMID 40580951.xlsx.txt was searched for c.3802del, p.Val1268Ter, p.V1268*, and 3802delG, with no exact entry found.

VCEP rule
* Missense: REVEL **\>.7333** * Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
  • Case normalization identifies NM_000051.4:c.3802del as NP_000042.3:p.(Val1268Ter)/p.(V1268*), a truncating deletion.
  • The case SpliceAI result is max delta 0.045, but it is outside the applicable PP3 scope for this truncating variant and was not used.
  • Suppl_TableS1_PMID 40580951.xlsx.txt was searched under c.3802del, p.Val1268Ter, p.V1268*, and 3802delG; no exact variant row was found.
Still missing
  • No exact c.3802del, p.Val1268Ter, p.V1268*, or 3802delG entry was found in Suppl_TableS1_PMID 40580951.xlsx.txt; this is not evidence that the variant's computational evidence is absent.
Sources
cspec ↗
PP4 VCEPNot applicable: the VCEP excludes PP4 for both ATM-related dominant cancer predisposition and recessive ataxia-telangiectasia. Details ▾Hide ▴
Reasoning

The VCEP marks PP4 not applicable: it says not to use PP4 for autosomal dominant ATM-related cancer predisposition because breast cancer has multiple genetic etiologies, and not to use it separately for autosomal recessive ataxia-telangiectasia because phenotype evidence is incorporated into the PM3/BP2 table.

VCEP rule
Autosomal Dominant: do not use as breast cancer is a disease with multiple genetic etiology (genetic heterogeneity) and there are no features that can readily distinguish hereditary from sporadic causes. Autosomal Recessive: do not use as a separate line of evidence. Such evidence is built into the Ataxia Telangiectasia PM3|BP2 table
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 PP4 instructions: AD PP4 is not used because breast cancer has multiple genetic etiologies; AR PP4 is not used separately because the evidence is built into the Ataxia-Telangiectasia PM3/BP2 table.
Sources
cspec ↗
BS2 VCEPNot applicable: the ATM VCEP excludes BS2 because ATM has incomplete penetrance. Details ▾Hide ▴
Reasoning

BS2 is not applicable under the ATM VCEP because the VCEP explicitly states not to use it: ATM has incomplete penetrance.

VCEP rule
Do not use: ATM has incomplete penetrance.
Evidence considered
  • ClinGen ATM VCEP CSPEC BS2 instructions: "Do not use: ATM has incomplete penetrance."
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP explicitly designates BS4 as not applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP specification explicitly marks BS4 as not applicable. Non-segregation evidence cannot be used for this criterion under the governing VCEP framework.

VCEP rule
Not Applicable
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC criteria entry for BS4: applicability is "Not Applicable".
Sources
cspec ↗
BP1 VCEPNot applicable: ATM has known missense pathogenic variants, and c.3802del is a nonsense/truncating variant rather than missense. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP1 not applicable and instructs not to use it because missense pathogenic variants are known for ATM. The current variant is a nonsense/truncating change and is not within BP1's missense-only concept.

VCEP rule
Do not use: Missense pathogenic variants are known for ATM
Evidence considered
  • ATM CSPEC BP1 instructions state: Do not use because missense pathogenic variants are known for ATM.
  • Case normalization identifies the consequence as p.(Val1268Ter), a nonsense variant.
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP marks BP3 Not Applicable, and this variant is a coding nonsense deletion rather than an in-frame repeat-region indel. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC entry marks BP3 as Not Applicable. In addition, this variant is a coding nonsense-producing deletion rather than an in-frame deletion or insertion in a repetitive region, so the BP3 criterion does not apply.

VCEP rule
Not Applicable
Evidence considered
  • ATM CSPEC criterion entry for BP3: applicability is Not Applicable.
  • The variant consequence is nonsense, p.Val1268Ter, not an in-frame deletion or insertion.
Sources
cspec ↗
BP4 N/ANot applicable: BP4 cannot clear the truncating protein effect of c.3802del, regardless of its SpliceAI max delta of 0.045. Details ▾Hide ▴
Reasoning

The variant is a truncating deletion, annotated as ATM c.3802del with p.(Val1268Ter)/p.(V1268*). Under the requested application of the ATM VCEP rule, BP4 on a frameshift or nonsense variant is not applicable: a low SpliceAI score does not negate the truncating protein effect. The available SpliceAI max delta of 0.045 is consequently not evidence for BP4. The governing full-text file Suppl_TableS1_PMID 40580951.xlsx.txt was searched for c.3802del, p.Val1268Ter, p.V1268*, and 3802delG, with no exact entry found.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • Case normalization identifies NM_000051.4:c.3802del as NP_000042.3:p.(Val1268Ter)/p.(V1268*), a truncating deletion.
  • The case SpliceAI result is max delta 0.045, but a no-impact splice prediction does not remove the truncating protein consequence and was not used for BP4.
  • Suppl_TableS1_PMID 40580951.xlsx.txt was searched under c.3802del, p.Val1268Ter, p.V1268*, and 3802delG; no exact variant row was found.
Still missing
  • No exact c.3802del, p.Val1268Ter, p.V1268*, or 3802delG entry was found in Suppl_TableS1_PMID 40580951.xlsx.txt; this is not evidence that the variant's computational evidence is absent.
Sources
cspec ↗
BP5 VCEPNot applicable: the VCEP prohibits BP5 because ATM's low penetrance and observed multiple pathogenic variants make this criterion unreliable. Details ▾Hide ▴
Reasoning

The VCEP marks BP5 not applicable and instructs not to use it because multiple pathogenic variants can occur without a noticeable phenotype difference and ATM's low penetrance makes coincident pathogenic variants more frequent. No BP5 assessment is permitted.

VCEP rule
Do not use: Cases with multiple pathogenic variants have been observed with no noticeable difference in phenotype (e.g. BRCA1 and BRCA2). In addition, ATM has low penetrance and will naturally occur with other pathogenic variants more frequently due to higher tolerance/presence in the general population.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 BP5 instructions: do not use because cases with multiple pathogenic variants have been observed with no noticeable phenotype difference and ATM has low penetrance.
Sources
cspec ↗
BP6 VCEPNot applicable: the VCEP explicitly prohibits BP6 use under its governing ATM specification. Details ▾Hide ▴
Reasoning

The VCEP explicitly marks BP6 as not applicable and instructs that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Benign assertions from reputable sources therefore cannot establish BP6 under this governing framework.

VCEP rule
This criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 BP6 instructions: this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous or deep intronic variants, whereas c.3802del is a truncating coding deletion. Details ▾Hide ▴
Reasoning

The ATM VCEP BP7 rule applies to synonymous and deep intronic variants, with its RNA path likewise limited to silent substitutions and intronic variants. ATM c.3802del is a truncating coding deletion producing p.(Val1268Ter)/p.(V1268*), so it lies outside BP7's applicability and no BP7 evidence is assessed.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • Case normalization identifies NM_000051.4:c.3802del as NP_000042.3:p.(Val1268Ter)/p.(V1268*), a truncating coding deletion.
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.3802del
Protein (HGVS p.)
NP_000042.3:p.(Val1268Ter)
GRCh38
chr11:108284280 AG>A
GRCh37
chr11:108155007 AG>A
Location and type
Exon 26 · nonsense
ClinVar
127374
COSMIC
COSV53739410

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 v4.1 135 / 1,613,134 alleles AF 8.37e-05 · 0 homozygotes · FAF 9.61e-05
gnomAD v2.1 11 / 282,542 alleles AF 3.89e-05 · 0 homozygotes · FAF 2.86e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 8.4e-05 · 135 / 1,613,134 alleles · 0 hom · FAF 9.6e-05
European (non-Finnish)132 / 1,179,266 0.00011
Admixed American3 / 60,006 5e-05
0 alternate alleles recorded in 8 other groups: Remaining individuals, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

gnomAD v2.1

AF 3.9e-05 · 11 / 282,542 alleles · 0 hom · FAF 2.9e-05
Admixed American3 / 35,406 8.5e-05
European (non-Finnish)8 / 128,978 6.2e-05
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 8.3688e-05; MAF= 0.00837%, 135/1613134 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000111934; MAF= 0.01119%, 132/1179266 alleles, homozygotes = 0); grpmax FAF= 9.614e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.89323e-05; MAF= 0.00389%, 11/282542 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.47314e-05; MAF= 0.00847%, 3/35406 alleles, homozygotes = 0); grpmax FAF= 2.858e-05.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -53 bp
0.001
SpliceAI acceptor gainat +104 bp
0.045
SpliceAI donor lossat +1 bp
0.008
SpliceAI donor gainat -262 bp
0.004
Pangolin splice lossmagnitude shown
-0.065
Pangolin splice gain
0.016

Other predictors

REVEL
Not available
BayesDel
Not available

How the predictions were used

PP3 N/ANot applicable: PP3's ATM splicing path covers silent, missense/in-frame, and qualifying intronic variants, not this truncating c.3802del variant. Details ▾Hide ▴
Reasoning

The variant is a truncating deletion, annotated as ATM c.3802del with p.(Val1268Ter)/p.(V1268*). The ATM VCEP PP3 rule limits its splicing path to silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites; this frameshift/nonsense variant is outside that scope. The available SpliceAI max delta of 0.045 is therefore not used for PP3. The governing full-text file Suppl_TableS1_PMID 40580951.xlsx.txt was searched for c.3802del, p.Val1268Ter, p.V1268*, and 3802delG, with no exact entry found.

VCEP rule
* Missense: REVEL **\>.7333** * Splicing: Predicted impact via splicing (SpliceAI **≥0.2**) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites.
Evidence considered
  • Case normalization identifies NM_000051.4:c.3802del as NP_000042.3:p.(Val1268Ter)/p.(V1268*), a truncating deletion.
  • The case SpliceAI result is max delta 0.045, but it is outside the applicable PP3 scope for this truncating variant and was not used.
  • Suppl_TableS1_PMID 40580951.xlsx.txt was searched under c.3802del, p.Val1268Ter, p.V1268*, and 3802delG; no exact variant row was found.
Still missing
  • No exact c.3802del, p.Val1268Ter, p.V1268*, or 3802delG entry was found in Suppl_TableS1_PMID 40580951.xlsx.txt; this is not evidence that the variant's computational evidence is absent.
Sources
cspec ↗
BP4 N/ANot applicable: BP4 cannot clear the truncating protein effect of c.3802del, regardless of its SpliceAI max delta of 0.045. Details ▾Hide ▴
Reasoning

The variant is a truncating deletion, annotated as ATM c.3802del with p.(Val1268Ter)/p.(V1268*). Under the requested application of the ATM VCEP rule, BP4 on a frameshift or nonsense variant is not applicable: a low SpliceAI score does not negate the truncating protein effect. The available SpliceAI max delta of 0.045 is consequently not evidence for BP4. The governing full-text file Suppl_TableS1_PMID 40580951.xlsx.txt was searched for c.3802del, p.Val1268Ter, p.V1268*, and 3802delG, with no exact entry found.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • Case normalization identifies NM_000051.4:c.3802del as NP_000042.3:p.(Val1268Ter)/p.(V1268*), a truncating deletion.
  • The case SpliceAI result is max delta 0.045, but a no-impact splice prediction does not remove the truncating protein consequence and was not used for BP4.
  • Suppl_TableS1_PMID 40580951.xlsx.txt was searched under c.3802del, p.Val1268Ter, p.V1268*, and 3802delG; no exact variant row was found.
Still missing
  • No exact c.3802del, p.Val1268Ter, p.V1268*, or 3802delG entry was found in Suppl_TableS1_PMID 40580951.xlsx.txt; this is not evidence that the variant's computational evidence is absent.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is restricted to synonymous or deep intronic variants, whereas c.3802del is a truncating coding deletion. Details ▾Hide ▴
Reasoning

The ATM VCEP BP7 rule applies to synonymous and deep intronic variants, with its RNA path likewise limited to silent substitutions and intronic variants. ATM c.3802del is a truncating coding deletion producing p.(Val1268Ter)/p.(V1268*), so it lies outside BP7's applicability and no BP7 evidence is assessed.

VCEP rule
* BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively. * BP7(RNA): Observed lack of aberrant RNA defect for silent substitutions and intronic variants. Variable weight applied depending on curator discretion of assay quality.
Evidence considered
  • Case normalization identifies NM_000051.4:c.3802del as NP_000042.3:p.(Val1268Ter)/p.(V1268*), a truncating coding deletion.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

8 paper records listed. 2 cited in the classification.

Cited in the classification

  • ATM mutations that cause ataxia-telangiectasia are breast cancer susceptibility alleles.
    Renwick A et al. · 2006 Aug
    The paper explicitly reports this allele as 3802delG in one familial breast-cancer case and classifies it as causing a premature truncation; it also notes prior reports in ataxia-telangiectasia families.
    → PVS1 · very strong → PM5 · supporting Names this variant
    PMID 16832357 ↗
    Source detail
    4 | 3802delG | Premature truncation | 1 | 0 All of the mutations are predicted to cause ataxia-telangiectasia, and seven of the nine mutations identified in cases have previously been reported in ataxia-telangiectasia families, including the two most common mutations in the UK, 5762ins137 and 3802delG.

    Location Table 1, Family 4; Results, paragraph beginning ‘We identified nine (2.04%) ATM mutations’

    Context ATM sequencing across the 62 coding exons and splice junctions in 443 familial breast-cancer cases and 521 controls.

  • DHPLC screening of ATM gene in Italian patients affected by ataxia-telangiectasia: fourteen novel ATM mutations.
    Magliozzi M et al. · 2006
    The paper explicitly reports the ATM deletion as 3802delG in exon 28, corresponding to the provided ATM c.3802del variant and resulting in p.(V1268*). It was identified in two patients with classical ataxia-telangiectasia and described as producing a truncated protein.
    → PVS1 · very strong → PM3 · moderate → PM5 · supporting Names this variant
    PMID 17124347 ↗
    Source detail
    28 AT42RM (het) 3802delG Deletion/Truncated protein [17] 28 AT105RM (hom) 3802delG Deletion/Truncated protein [17]

    Location Table 3, exon 28; Results, paragraph 3

    Context DHPLC screening and bidirectional sequencing of all 62 ATM coding exons in 22 unrelated patients with classical ataxia-telangiectasia.

Other recorded publications

  • ATM Mutations in Cancer: Therapeutic Implications.
    No paper-specific finding is recorded.
    PMID 27413114 ↗
  • Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
    No paper-specific finding is recorded.
    PMID 30348496 ↗
  • Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.
    No paper-specific finding is recorded.
    PMID 30553448 ↗
  • Splicing defects in the ataxia-telangiectasia gene, ATM: underlying mutations and consequences.
    Teraoka SN et al. · 1999
    No paper-specific finding is recorded.
    PMID 10330348 ↗
  • Spectrum of ATM gene mutations in a hospital-based series of unselected breast cancer patients.
    Dörk T et al. · 2001
    No paper-specific finding is recorded.
    PMID 11606401 ↗
  • Independent mutational events are rare in the ATM gene: haplotype prescreening enhances mutation detection rate.
    Mitui M et al. · 2003
    No paper-specific finding is recorded.
    PMID 12815592 ↗

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

gnomAD v4.1 135 / 1,613,134 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.045 Open source ↗
ClinVar 39 Pathogenic · 1 Likely pathogenic · 1 pathogenic 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= 8.3688e-05; MAF= 0.00837%, 135/1613134 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000111934; MAF= 0.01119%, 132/1179266 alleles, homozygotes = 0); grpmax FAF= 9.614e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 3.89323e-05; MAF= 0.00389%, 11/282542 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 8.47314e-05; MAF= 0.00847%, 3/35406 alleles, homozygotes = 0); grpmax FAF= 2.858e-05.

gnomAD-Canada

Not available in gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (39 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 127374)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.04).

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Somatic

This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV53739410, n = 4 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.