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ATMc.4850T>CUncertain significance
Print report
Variant interpretation report

ATM c.4850T>C, p.Leu1617Pro

NM_000051.4:c.4850T>C NP_000042.3:p.(Leu1617Pro) Missense · exon 32 View identifiers
Classification
Uncertain significance

Variant description:

The ATM NM_000051.4:c.4850T>C (NP_000042.3:p.(Leu1617Pro)) missense variant has not previously been reported in somatic cancers (COSMIC). Experimental evidence: Table S1 directly measures c.4850T>C as Non-functional with High confidence and DeepATM_predicted=No. Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS). This variant is considered to be a Variant of Uncertain Significance (VUS) by the VCEP (ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen; ClinVar ID 1018946).

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

Uncertain.The recorded classification is uncertain significance.

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: 3 Benign evidence criteria: 1
Pathogenic criteria applied · 3
PS3Supporting
PS3 · supporting

Met at Supporting: Table S1 directly measures c.4850T>C as Non-functional with High confidence and DeepATM_predicted=No.

PM2Supporting
PM2 · supporting

Met at Supporting: highest gnomAD subpopulation AF is 8.475107760995181e-07 (0.0000847511%), below the VCEP threshold of 0.001%.

PP3Supporting
PP3 · supporting

Met: REVEL 0.901 exceeds the ATM VCEP PP3 missense threshold of >0.7333.

Benign criteria applied · 1
BP4Supporting
BP4 · supporting

Met: SpliceAI max delta 0.023 is below the ATM VCEP BP4 no-impact threshold of <=0.1.

Recorded classification: Uncertain significance

VUS: PS3, PM2, PP3, and BP4 are supporting, but the ATM VCEP's Rule19 requires one very strong and exactly one listed supporting criterion for Likely Pathogenic.

02The sources

Evidence at a glance

Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.

No screenshot for this evidence
REVEL score
0.901 recorded score

Recorded REVEL score: 0.901. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3, BP4 →
ClinVar submissions
2 reported laboratory submissions

1 Uncertain significance · 1 Likely pathogenic. ClinVar API review status: reviewed by expert panel.

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 · PS3 → 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 v1.6, with the data and sources behind each one.

28 criteria with recorded statuses: 4 met · 1 not met · 7 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

For the requested consequence criteria, the ATM VCEP framework makes PVS1 inapplicable to this missense substitution, PM4 applicable only to stop-loss variants, and BP3 explicitly not applicable.

Among the requested codon, residue, and domain criteria, PS1 cannot be assessed without a documented previously established pathogenic comparator producing the same amino-acid change; PM1, PM5, PP2, and BP1 are not applicable under the ATM VCEP v1.6 rules.

Functional evidence is directionally damaging: the exact Sun et al. 2025 Table S1 row is a high-confidence direct prime-editing result classified Non-functional, supporting PS3_Supporting and not BS3.

Only PS4 is applicable under the ATM VCEP among the requested phenotype-prevalence assertions; available literature documents one affected carrier but no qualifying case-control comparison, so PS4 is not assessed.

PP4, PP5, BP5, and BP6 are not applicable under the VCEP's explicit criterion-specific instructions.

PP3 and BP4 are both evaluated from their distinct VCEP-named predictor paths: REVEL supports PP3, while SpliceAI supports BP4; the same prediction is not counted in both criteria.

BP7 is not applicable because the variant is missense.

Met · 4

PS3 SupportingVCEPMet at Supporting: Table S1 directly measures c.4850T>C as Non-functional with High confidence and DeepATM_predicted=No. Details ▾Hide ▴
Reasoning

The exact variant row in Sun et al. 2025 Supplementary Table S1 (Table S1, row 15467; c.4850T>C, L1617P) reports Classification=Non-functional, Confidence=High, and DeepATM_predicted=No. Under the VCEP's file-specific rule, this is a direct prime-editing measurement rather than a computational prediction and supports PS3 at Supporting strength. The VCEP-approved ATM assay methodology table was searched for c.4850T>C, p.Leu1617Pro, and p.L1617P and contains no variant-specific entry. PMID:22649200 was also reviewed because it reports this exact variant in patient AT 6, but its absence of residual ATM protein/activity in patient-derived cells is phenotypic patient material and is not used as PS3 functional evidence under the VCEP rule.

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
  • Sun et al. 2025, Supplementary Table S1, row 15467: cHGVS_nomenclature=c.4850T>C; Protein_change=L1617P; Variant_consequence=Missense; Classification=Non-functional; Confidence=High; DeepATM_predicted=No; Combined_score=-2.40621968220889.
  • The VCEP's file-specific PS3/BS3 rule states that DeepATM_predicted=No with High, Medium-high, or Medium confidence is a direct prime-editing measurement, and Classification=Non-functional supports PS3_Supporting.
  • The approved-assay calibration file was searched under c.4850T>C, p.Leu1617Pro, and p.L1617P; no variant-specific row was found.
  • PMID:22649200, Table I, patient AT 6, reports c.4850T>C; p.(Leu1617Pro) with no residual ATM protein and no measured residual ATM activity; this patient-derived phenotypic result was excluded as PS3 evidence because the VCEP says lack of ATM activity in cells from an affected patient is not functional data.
Still missing
  • No entry for c.4850T>C, p.Leu1617Pro, or p.L1617P was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; that file is an assay-methodology calibration table, not a variant-results table.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗PMID:22649200 ↗
PM2 SupportingVCEPMet at Supporting: highest gnomAD subpopulation AF is 8.475107760995181e-07 (0.0000847511%), below the VCEP threshold of 0.001%. Details ▾Hide ▴
Reasoning

The ATM VCEP applies PM2 at Supporting strength when the frequency is <=0.001% in the gnomAD subpopulation with the highest frequency. gnomAD v4.1 reports the highest observed subpopulation AF as 8.475107760995181e-07 (0.0000847511%), in European non-Finnish individuals, with 1/1,179,926 alleles and 0 homozygotes; this is below 0.001%. The gnomAD v2.1 and v3.1 non-cancer queries were absent, but the VCEP does not specify a non-cancer-only population source, so the default all-comers gnomAD v4.1 data are used.

VCEP rule
Frequency <=.001% in gnomAD subpopulation with the highest frequency ... Exception: If >0.001% but n=1 in a single subpopulation (not present in any other subpopulation), that is sufficiently rare and PM2_supporting would apply.
Evidence considered
  • ATM VCEP v1.6 CSPEC PM2 rule: frequency <=0.001% in the gnomAD subpopulation with the highest frequency; the VCEP assigns PM2 Supporting strength.
  • gnomAD v4.1 all-comers data: total AF 6.195717767707671e-07 (1/1,614,018 alleles; homozygotes 0); highest observed subpopulation European non-Finnish AF 8.475107760995181e-07 (0.0000847511%), 1/1,179,926 alleles, homozygotes 0.
  • The available gnomAD v2.1 non-cancer and gnomAD v3.1 non-cancer queries were absent; the ATM VCEP PM2 text does not require a non-cancer-only or exome-only source, so all-comers gnomAD v4.1 is the applicable default.
Sources
cspec ↗gnomad_v4 ↗
PP3 SupportingVCEPMet: REVEL 0.901 exceeds the ATM VCEP PP3 missense threshold of >0.7333. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the ATM VCEP missense PP3 path applies. The VCEP specifies PP3 Supporting for missense variants with REVEL >.7333. REVEL is 0.901, exceeding the governing cutoff. The VCEP Supplementary Table S1 row for c.4850T>C independently reports REVEL 0.901; its other computational values are treated only as corroboration and are not double-counted. SpliceAI max delta is 0.023, below the separate PP3 splicing threshold of >=0.2, so no splice-based PP3 is assigned.

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
  • ATM VCEP v1.6 PP3 rule: Missense: REVEL >.7333; Splicing: Predicted impact via splicing (SpliceAI >=0.2) for silent, missense/in-frame and for intronic variants outside donor and acceptor 1,2 sites.
  • Local REVEL lookup for NM_000051.4:c.4850T>C (NP_000042.3:p.(Leu1617Pro)): REVEL score 0.901.
  • Sun et al. 2025 Supplementary Table S1, exact row ATM c.4850T>C / L1617P: REVEL 0.901, Classification Non-functional, Confidence High, DeepATM_predicted No; the table's computational prediction values are corroborative only for PP3/BP4.
  • SpliceAI result for NM_000051.4:c.4850T>C: max delta score 0.023, which does not reach the ATM VCEP PP3 splicing threshold of >=0.2.
Sources
cspec ↗revelvcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP4 SupportingVCEPMet: SpliceAI max delta 0.023 is below the ATM VCEP BP4 no-impact threshold of <=0.1. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, and the ATM VCEP BP4 rule includes a splicing path for missense variants. That path assigns BP4 Supporting for no predicted splice impact via SpliceAI <=0.1. The observed SpliceAI maximum delta score is 0.023, which is below 0.1. The missense REVEL value of 0.901 does not meet the separate BP4 missense cutoff of <=0.249, so BP4 is assigned only from the VCEP-named splicing prediction and is not double-counted with the PP3 REVEL prediction.

VCEP rule
* Missense: REVEL score **\≤.249** * Splicing: No predicted impact via splicing (SpliceAI **\≤0.1**).
Evidence considered
  • ATM VCEP v1.6 BP4 rule: Missense: REVEL <=.249; Splicing: No predicted impact via splicing (SpliceAI <=0.1).
  • SpliceAI result for NM_000051.4:c.4850T>C: DS_AG 0.000, DS_AL 0.023, DS_DG 0.001, DS_DL 0.023; max delta score 0.023.
  • Local REVEL lookup for NM_000051.4:c.4850T>C: REVEL score 0.901, which does not satisfy the separate BP4 missense cutoff <=0.249; therefore BP4 is based only on the named splicing path.
  • Sun et al. 2025 Supplementary Table S1, exact row ATM c.4850T>C / L1617P: REVEL 0.901 and computational corroboration values; this row does not alter the VCEP BP4 splice threshold or replace the SpliceAI result.
Sources
cspec ↗spliceai ↗revelvcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗

Not met · 1 · evaluated, threshold not reached

BS3 VCEPNot met: Table S1 directly classifies c.4850T>C as Non-functional, not Functional, so the VCEP rescue requirement for BS3 is not satisfied. Details ▾Hide ▴
Reasoning

The exact variant row in Sun et al. 2025 Supplementary Table S1 reports Classification=Non-functional, Confidence=High, and DeepATM_predicted=No, which is direct prime-editing evidence in the damaging direction and does not show rescue of an ATM-specific feature or radiosensitivity. Therefore the VCEP BS3 rule is not satisfied. The VCEP-approved ATM assay methodology table was searched for c.4850T>C, p.Leu1617Pro, and p.L1617P and contains no variant-specific entry. The patient-derived result in PMID:22649200 is not used as BS3 because the VCEP excludes general patient-cell ATM activity as functional evidence.

VCEP rule
Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.
Evidence considered
  • Sun et al. 2025, Supplementary Table S1, row 15467: cHGVS_nomenclature=c.4850T>C; Protein_change=L1617P; Classification=Non-functional; Confidence=High; DeepATM_predicted=No; Combined_score=-2.40621968220889.
  • The VCEP BS3 Supporting rule requires that a variant rescue either an ATM-specific feature or radiosensitivity; the direct row instead reports Non-functional.
  • The approved-assay calibration file was searched under c.4850T>C, p.Leu1617Pro, and p.L1617P; no variant-specific row was found.
  • PMID:22649200, Table I, patient AT 6, reports the exact variant with no residual ATM protein and no measured residual ATM activity; this is not evidence of functional rescue and is excluded from BS3 under the VCEP's patient-cell functional-evidence restriction.
Still missing
  • No entry for c.4850T>C, p.Leu1617Pro, or p.L1617P was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx; that file is an assay-methodology calibration table, not a variant-results table.
Sources
cspec ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗PMID:22649200 ↗

Not assessed · 7 · no assessment recorded

PS1 VCEPNot assessed: no previously established pathogenic variant with the same amino-acid change was identified for comparison under the ATM PS1 rule. Details ▾Hide ▴
Reasoning

The ATM VCEP defines PS1 as the same amino acid change as a previously established pathogenic variant, with missense use requiring splicing to be ruled out for both alterations. The governing ATM_PS1_1.6.pdf was searched for c.4850T>C, p.Leu1617Pro, and p.L1617P; no entry was found. The available exact-variant paper reports p.Leu1617Pro in patient AT 6, but does not establish a different nucleotide change producing the same amino-acid substitution. Therefore the required comparator evidence is unavailable and PS1 cannot be assessed.

VCEP rule
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change • Missense: This rule may be applied only when a splice defect is ruled out for both alterations either by RNA analysis and/or in silico splice predictions
Evidence considered
  • ATM_PS1_1.6.pdf: searches for c.4850T>C, p.Leu1617Pro, and p.L1617P found no matching entry.
  • PMID:22649200, Table I, patient AT 6: c.4850T>C; p.(Leu1617Pro) was reported with c.6916delAG; p.2306fs; no residual ATM protein or activity was detected, but the paper does not provide a same-amino-acid pathogenic comparator.
  • The variant is a missense change and SpliceAI max delta is 0.023, but PS1 remains unassessed because the required same-amino-acid pathogenic reference variant is not available.
Still missing
  • No entry for c.4850T>C, p.Leu1617Pro, or p.L1617P was found in ATM_PS1_1.6.pdf; a documented pathogenic comparator producing p.Leu1617Pro is still needed.
Sources
vcep_atm_ps1_1_6 ↗PMID:22649200 ↗
PS4 VCEPNot assessed: one affected patient is reported, but no control comparison, p-value, odds ratio, or 95% confidence interval is available for the VCEP PS4 rule. Details ▾Hide ▴
Reasoning

The VCEP makes PS4 applicable only for a case-control study with p-value ≤.05 and either an odds ratio, hazard ratio, or relative risk ≥2, or a lower 95% confidence interval ≥1.5. PMID:22649200 reports the exact variant in one affected patient (AT 6) with a second ATM variant, but it provides no unaffected/population control comparison, case-control counts, p-value, odds ratio, relative risk, hazard ratio, or confidence interval. The other reviewed papers were general ataxia/cancer-predisposition material or did not mention this variant, and literature_pass.json has no ai_classified_papers entry to verify as PS4. Therefore the VCEP PS4 rule cannot be evaluated from the available evidence.

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 CSPEC PS4 rule: case-control studies require p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥2 or lower 95% CI ≥1.5).
  • Carney et al. 2012, Table I, patient AT 6: ATM c.4850T>C; p.(Leu1617Pro) was reported in one affected classical ataxia-telangiectasia patient, with c.6916delAG; p.2306fs as the second ATM variant; no control group or case-control statistic was reported.
  • The reviewed papers PMID:26896183, PMID:24418350, and PMID:25394175 did not provide variant-specific case-control evidence; literature_pass.json ai_classified_papers was empty.
Still missing
  • A case-control dataset or matched-ancestry control comparison for c.4850T>C is needed, including p-value and OR/RR/HR or its lower 95% confidence limit.
Sources
cspec ↗PMID:22649200 ↗PMID:26896183 ↗PMID:24418350 ↗PMID:25394175 ↗
PM3 VCEPNot assessed: one confident A-T proband contributes 2.0 phase-unknown points, but the reported second variant's VCEP classification and phase are unconfirmed. Details ▾Hide ▴
Reasoning

The exact variant is reported in PMID:22649200 in patient AT 6, a 14-year-11-month-old male with classical ataxia-telangiectasia, alongside ATM c.6916delAG; p.2306fs. The VCEP PM3 table assigns a confident-phenotype proband 2.0 points when the co-occurring pathogenic variant is in phase unknown, which would correspond to PM3 Moderate, but the available report does not establish that c.6916delAG; p.2306fs was classified pathogenic or likely pathogenic under the VCEP, and it does not establish phase. The governing ATM_PM3_BP2_1.6.pdf was searched for c.4850T>C, p.Leu1617Pro, and p.L1617P; no variant-specific pre-assigned PM3 code was found. Therefore the VCEP PM3 path cannot be completed without confirming the second variant's VCEP classification and phase or qualifying phase-unknown assumptions.

VCEP rule
For recessive disorders, detected in trans with a pathogenic variant ... Phenotype confident ... 4.0 ... 2.0 ... 1.0 ... 2.0 ... PM3_ ... 1.0 ... 2.0 ... 4.0 ... 8.0
Evidence considered
  • ATM_PM3_BP2_1.6.pdf: PM3 rule requires a recessive-disorder observation in trans with a pathogenic variant; its table assigns 2.0 points for a confident phenotype with phase unknown and PM3 Moderate at 2.0 points.
  • PMID:22649200, Table I, patient AT 6: AT 6 was a 14-year-11-month-old male with no residual ATM protein, and the row lists c.6916delAG; p.2306fs with c.4850T>C; p.(Leu1617Pro).
  • The case evidence does not document phase or a VCEP classification for c.6916delAG; p.2306fs, so the table's 2.0-point path cannot be applied as a completed PM3 assessment.
Still missing
  • ATM_PM3_BP2_1.6.pdf was searched for c.4850T>C, p.Leu1617Pro, and p.L1617P; no variant-specific entry or pre-assigned PM3 code was found.
  • PMID:22649200 reports the second ATM variant c.6916delAG; p.2306fs, but the available evidence does not provide its VCEP pathogenic/likely pathogenic classification or establish phase.
  • No additional qualifying affected-proband records with confirmed trans phase were identified in the reviewed case evidence.
Sources
vcep_atm_pm3_bp2_1_6 ↗PMID:22649200 ↗
PP1 VCEPNot assessed: one affected patient carried the variant and c.6916delAG, but no affected-relative segregation or parental-phase data were reported. Details ▾Hide ▴
Reasoning

PP1 is applicable only on the ATM VCEP's autosomal recessive path when affected relatives have both variants identified in the proband. PMID:22649200 reports the exact variant in one affected A-T patient (AT 6), together with c.6916delAG; p.2306fs, but provides no affected-relative segregation, parental phase, or meiosis data. The available report therefore cannot establish segregation in one or more affected relatives or assign PP1 strength.

VCEP rule
AR Condition: Affected relatives must have both variants identified in proband. ... AR Condition: Segregation in 1 affected relative ... AR Condition: Segregation in 2 affected relatives ... AR Condition: Segregation in ≥3 affected relatives
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 PP1 instruction: AR affected relatives must have both variants identified in the proband.
  • ClinGen HBOP ATM VCEP v1.6 PP1 strength table: supporting requires segregation in 1 affected relative, moderate requires 2, and strong requires at least 3 affected relatives.
  • Carney et al., PMID:22649200, Table I, patient AT 6: the exact ATM variant c.4850T>C; p.(Leu1617Pro) was reported in a 14-year-11-month-old male with c.6916delAG; p.2306fs; the report does not document affected-relative segregation or parental phase.
Still missing
  • Affected relatives with both ATM variants identified in the proband are not documented.
  • Parental testing, phase, and meiosis information are not available.
Sources
cspec ↗PMID:22649200 ↗
BA1 VCEPNot assessed: the required gnomAD Grpmax Filtering AF is unavailable, although the highest observed subpopulation AF is 8.475107760995181e-07. Details ▾Hide ▴
Reasoning

The ATM VCEP defines BA1 using the gnomAD Grpmax Filtering AF metric (>0.5%). gnomAD v4.1 reports a highest observed subpopulation AF of 8.475107760995181e-07 (1/1,179,926 alleles; homozygotes 0), but the case evidence does not provide the required Grpmax Filtering AF value, so the VCEP rule cannot be evaluated exactly.

VCEP rule
Grpmax Filtering AF >.5% in gnomAD
Evidence considered
  • ATM VCEP v1.6 CSPEC BA1 rule: Grpmax Filtering AF >0.5% in gnomAD.
  • gnomAD v4.1 all-comers data: total AF 6.195717767707671e-07 (1/1,614,018 alleles; homozygotes 0); highest observed subpopulation was European non-Finnish at AF 8.475107760995181e-07 (1/1,179,926 alleles; homozygotes 0); exact Grpmax Filtering AF was null/unavailable.
Still missing
  • Exact gnomAD Grpmax Filtering AF for the variant
Sources
cspec ↗gnomad_v4 ↗
BS1 VCEPNot assessed: the required gnomAD Grpmax Filtering AF is unavailable, although the highest observed subpopulation AF is 8.475107760995181e-07. Details ▾Hide ▴
Reasoning

The ATM VCEP defines BS1 using the gnomAD Grpmax Filtering AF metric (>0.05%). gnomAD v4.1 reports a highest observed subpopulation AF of 8.475107760995181e-07 (1/1,179,926 alleles; homozygotes 0), but the case evidence does not provide the required Grpmax Filtering AF value, so the VCEP rule cannot be evaluated exactly.

VCEP rule
Grpmax Filtering AF >.05% in gnomAD
Evidence considered
  • ATM VCEP v1.6 CSPEC BS1 rule: Grpmax Filtering AF >0.05% in gnomAD.
  • gnomAD v4.1 all-comers data: total AF 6.195717767707671e-07 (1/1,614,018 alleles; homozygotes 0); highest observed subpopulation was European non-Finnish at AF 8.475107760995181e-07 (1/1,179,926 alleles; homozygotes 0); exact Grpmax Filtering AF was null/unavailable.
Still missing
  • Exact gnomAD Grpmax Filtering AF for the variant
Sources
cspec ↗gnomad_v4 ↗
BP2 VCEPNot assessed: the available affected-patient report does not establish cis phase or an unaffected adult observation required for the BP2 points table. Details ▾Hide ▴
Reasoning

The VCEP BP2 rule concerns an 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 negative points assigned for an unaffected non-A-T adult. The available exact-variant report is an affected A-T patient and does not establish cis phase; it therefore does not provide a qualifying BP2 observation. No unaffected adult observation or cis observation for c.4850T>C; p.Leu1617Pro was identified in the reviewed evidence.

VCEP rule
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern. ... Points per Unaffected (non-A-T) Adult (>18yo) Proband (BP2)
Evidence considered
  • ATM_PM3_BP2_1.6.pdf: BP2 applies to an observation in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or in cis with a pathogenic variant in any inheritance pattern; the negative-point table is for an unaffected non-A-T adult proband.
  • PMID:22649200, Table I, patient AT 6: the exact variant appears in an affected classical A-T patient, not an unaffected non-A-T adult, and the row does not establish cis phase.
Still missing
  • ATM_PM3_BP2_1.6.pdf was searched for c.4850T>C, p.Leu1617Pro, and p.L1617P; no variant-specific entry or pre-assigned BP2 code was found.
  • No qualifying unaffected non-A-T adult observation and no confirmed cis observation were available for BP2.
Sources
vcep_atm_pm3_bp2_1_6 ↗PMID:22649200 ↗
Not applicable · 16· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.4850T>C is a missense variant, whereas the ATM PVS1 guide limits this criterion to null variant classes such as nonsense, frameshift, splice-site, initiation-codon, or exon-deletion variants. Details ▾Hide ▴
Reasoning

PVS1 is not applicable. NM_000051.4:c.4850T>C is a missense substitution, NP_000042.3:p.(Leu1617Pro), in exon 32, not a nonsense, frameshift, canonical splice-site, initiation-codon, or exon-deletion variant. The ATM VCEP PVS1 guide defines PVS1 for null variant classes and directs assessment through its decision tree; no PVS1 missense path applies here. The searched file ATM_PVS1_1.6.pdf contains no entry for c.4850T>C, p.Leu1617Pro, or p.L1617P. The exact variant is reported in PMID:22649200 in patient AT 6 with a second frameshift allele and absent ATM protein, but that compound-genotype observation does not convert this missense variant into a PVS1-eligible null variant.

VCEP rule
Null variant (nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, single or multi-exon deletion) in a gene where loss of function (LOF) is a known mechanism of disease ... PVS1 can be applied as per the below decision tree.
Evidence considered
  • Case consequence evidence: NM_000051.4:c.4850T>C produces NP_000042.3:p.(Leu1617Pro)/p.(L1617P), a missense substitution in exon 32.
  • ATM_PVS1_1.6.pdf, PVS1 definition and decision-tree entry: PVS1 is for null variants including nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, and single or multi-exon deletion; the guide states that PVS1 is applied according to its decision tree.
  • ATM_PVS1_1.6.pdf was searched under c.4850T>C, p.Leu1617Pro, and p.L1617P; no matching variant entry was found.
  • PMID:22649200, Table I, patient AT 6: c.4850T>C; p.(Leu1617Pro) was reported with c.6916delAG; p.2306fs, with no residual ATM protein detected; this compound-genotype observation is not used as PVS1 evidence for the missense allele.
Still missing
  • ATM_PVS1_1.6.pdf was searched for c.4850T>C, p.Leu1617Pro, and p.L1617P; no entry for this variant was found.
Sources
cspec ↗vcep_atm_pvs1_1_6 ↗PMID:22649200 ↗
PS2 VCEPNot applicable: the ATM VCEP excludes PS2 for autosomal dominant and autosomal recessive disease because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PS2 not applicable and instructs that de novo evidence is not used for either autosomal dominant or autosomal recessive disease because informative de novo occurrences have not been observed and de novo autosomal recessive disease is unlikely to be informed by phase.

VCEP rule
Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 criterion entry: PS2 applicability is not applicable; its instruction excludes PS2 for AD or AR disease.
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP marks PM1 Not Applicable, so residue 1617 is not evaluated through a PM1 domain or hotspot route. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC marks PM1 Not Applicable. No PM1 domain or hotspot route is available under this governing VCEP for this missense variant.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP v1.6 CSPEC criterion entry for PM1: applicability is Not Applicable.
Sources
cspec ↗
PM4 N/ANot applicable: p.(Leu1617Pro) is a missense change, and the ATM VCEP PM4 rule applies only to stop-loss variants. Details ▾Hide ▴
Reasoning

PM4 is not applicable because the ATM VCEP specifies PM4 for stop-loss variants, while NM_000051.4:c.4850T>C is a missense substitution producing p.(Leu1617Pro), not a stop-loss variant.

VCEP rule
Use for stop-loss variants.
Evidence considered
  • ATM VCEP CSPEC PM4 entry: Use for stop-loss variants.
  • Case consequence evidence: NM_000051.4:c.4850T>C is missense, encoding NP_000042.3:p.(Leu1617Pro)/p.(L1617P).
Sources
cspec ↗
PM5 N/ANot applicable: PM5 is limited to NMD-prone truncating or qualifying observed splice variants upstream of p.Leu3048, whereas this variant is missense. Details ▾Hide ▴
Reasoning

The ATM VCEP PM5 rule is restricted to NMD-prone truncating variants with premature termination codons upstream of p.Leu3048, with a separate observed-RNA pathway for splice variants. This variant is missense, so the rule does not apply regardless of same-residue substitutions.

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 * Splice Variants: Apply only to observed (not predicted) NMD-prone, truncating variants receiving PVS1(RNA) (must be at VeryStrong with high-quality RNA data) with premature termination codons upstream of p.Leu3048. This is not applicable for predicted splice impact without RNA data or PVS1(RNA) at reduced strength.
Evidence considered
  • ATM VCEP v1.6 PM5 rule: DNA variants must be NMD-prone truncating variants receiving PVS1 VeryStrong with premature termination codons upstream of p.Leu3048; the splice pathway requires observed RNA data and PVS1(RNA) VeryStrong.
Sources
cspec ↗
PM6 VCEPNot applicable: the ATM VCEP excludes assumed de novo evidence for autosomal dominant and autosomal recessive disease in this framework. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PM6 not applicable and gives the same disease-scope restriction as PS2; assumed de novo evidence without confirmed maternity and paternity is therefore not used for this ATM interpretation.

VCEP rule
Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 criterion entry: PM6 applicability is not applicable; its instruction excludes PM6 for AD or AR disease.
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP marks PP2 Not Applicable, so no gene-level missense-enrichment evidence is assigned. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC marks PP2 Not Applicable. No gene-level missense-enrichment route may be applied under this governing framework.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP v1.6 CSPEC criterion entry for PP2: applicability is Not Applicable.
Sources
cspec ↗
PP4 VCEPNot applicable: the ATM VCEP excludes PP4 for breast cancer and incorporates autosomal-recessive phenotype evidence into PM3/BP2 instead. Details ▾Hide ▴
Reasoning

The ATM VCEP marks PP4 not applicable: for autosomal dominant disease, breast cancer has multiple genetic etiologies and no readily distinguishing hereditary features; for autosomal recessive disease, phenotype evidence is incorporated into the ATM PM3/BP2 table rather than used as a separate PP4 line of evidence.

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: autosomal dominant breast cancer is genetically heterogeneous without readily distinguishing features, and autosomal recessive phenotype evidence is built into the PM3/BP2 table.
Sources
cspec ↗
PP5 VCEPNot applicable: the ATM VCEP explicitly prohibits PP5, regardless of pathogenic reports from reputable sources. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly marks PP5 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Variant-specific or source-level pathogenic reports therefore cannot activate PP5 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 PP5 entry: applicability is Not Applicable for this VCEP and the criterion is not for use.
Sources
cspec ↗
BS2 VCEPNot applicable: the ATM VCEP explicitly marks BS2 as not applicable. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BS2 as not applicable. No BS2 assessment is made.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP v1.6 CSPEC entry for BS2: Applicability = Not Applicable.
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP states that informative lack-of-co-segregation instances in ataxia-telangiectasia families are too rare to receive weight. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BS4 not applicable. Its autosomal recessive instruction states that informative lack-of-co-segregation instances in ataxia-telangiectasia families are too rare to receive weight at this time; no BS4 evidence can be assigned.

VCEP rule
AR Condition: Informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 criterion entry: BS4 applicability is not applicable; its AR instruction excludes weighting informative lack of co-segregation in A-T families.
Sources
cspec ↗
BP1 VCEPNot applicable: the ATM VCEP marks BP1 Not Applicable, so no benign missense-gene or domain evidence is assigned. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC marks BP1 Not Applicable. No benign evidence based on a missense-intolerant gene or a benign domain route may be assigned under this governing framework.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP v1.6 CSPEC criterion entry for BP1: applicability is Not Applicable.
Sources
cspec ↗
BP3 VCEPNot applicable: the ATM VCEP explicitly marks BP3 as Not Applicable, regardless of this missense variant's repeat-region context. Details ▾Hide ▴
Reasoning

BP3 is not applicable under the ATM VCEP CSPEC entry, which explicitly marks BP3 as Not Applicable. No repeat-region or in-frame-deletion assessment can override that criterion-level VCEP applicability decision.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC BP3 entry: applicability is listed as Not Applicable.
Sources
cspec ↗
BP5 VCEPNot applicable: the ATM VCEP prohibits BP5 because multiple pathogenic variants may coexist without a noticeable phenotype difference in this low-penetrance gene. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BP5 not applicable and instructs curators not to use it because cases with multiple pathogenic variants have been observed without a noticeable phenotype difference; ATM's low penetrance also makes co-occurrence with other pathogenic variants more frequent.

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 BP5 because multiple pathogenic variants have been observed with no noticeable phenotype difference and ATM has low penetrance.
Sources
cspec ↗
BP6 VCEPNot applicable: the ATM VCEP explicitly prohibits BP6, regardless of benign reports from reputable sources. Details ▾Hide ▴
Reasoning

The ATM VCEP explicitly marks BP6 as not applicable and states that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee. Benign reports therefore cannot activate 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 entry: applicability is Not Applicable for this VCEP and the criterion is not for use.
Sources
cspec ↗
BP7 N/ANot applicable: BP7 is restricted by the ATM VCEP to synonymous and deep intronic variants, not missense substitutions. Details ▾Hide ▴
Reasoning

The variant is missense. The ATM VCEP BP7 applicability statement limits BP7 to synonymous and deep intronic variants, and the RNA path likewise addresses silent substitutions and intronic variants. Therefore BP7 is not applicable regardless of the available SpliceAI result.

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
  • ATM VCEP v1.6 BP7 rule: BP7 is 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) concerns silent substitutions and intronic variants.
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.4850T>C
Protein (HGVS p.)
NP_000042.3:p.(Leu1617Pro)
GRCh38
chr11:108295000 T>C
GRCh37
chr11:108165727 T>C
Location and type
Exon 32 · missense
ClinVar
1018946

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 1 / 1,614,018 alleles AF 6.2e-07 · 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 6.2e-07 · 1 / 1,614,018 alleles · 0 hom
European (non-Finnish)1 / 1,179,926 8.5e-07
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.

Statements

gnomAD v4.1

This variant is present in gnomAD v4.1 (AF= 6.19572e-07; MAF= 0.00006%, 1/1614018 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47511e-07; MAF= 0.00008%, 1/1179926 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat -73 bp
0.023
SpliceAI acceptor gainat -118 bp
0.000
SpliceAI donor lossat +59 bp
0.023
SpliceAI donor gainat -53 bp
0.001
Pangolin splice lossmagnitude shown
-0.034
Pangolin splice gain
0.005

Other predictors

REVEL
0.901
BayesDel
0.321

How the predictions were used

PP3 SupportingVCEPMet: REVEL 0.901 exceeds the ATM VCEP PP3 missense threshold of >0.7333. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, so the ATM VCEP missense PP3 path applies. The VCEP specifies PP3 Supporting for missense variants with REVEL >.7333. REVEL is 0.901, exceeding the governing cutoff. The VCEP Supplementary Table S1 row for c.4850T>C independently reports REVEL 0.901; its other computational values are treated only as corroboration and are not double-counted. SpliceAI max delta is 0.023, below the separate PP3 splicing threshold of >=0.2, so no splice-based PP3 is assigned.

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
  • ATM VCEP v1.6 PP3 rule: Missense: REVEL >.7333; Splicing: Predicted impact via splicing (SpliceAI >=0.2) for silent, missense/in-frame and for intronic variants outside donor and acceptor 1,2 sites.
  • Local REVEL lookup for NM_000051.4:c.4850T>C (NP_000042.3:p.(Leu1617Pro)): REVEL score 0.901.
  • Sun et al. 2025 Supplementary Table S1, exact row ATM c.4850T>C / L1617P: REVEL 0.901, Classification Non-functional, Confidence High, DeepATM_predicted No; the table's computational prediction values are corroborative only for PP3/BP4.
  • SpliceAI result for NM_000051.4:c.4850T>C: max delta score 0.023, which does not reach the ATM VCEP PP3 splicing threshold of >=0.2.
Sources
cspec ↗revelvcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP4 SupportingVCEPMet: SpliceAI max delta 0.023 is below the ATM VCEP BP4 no-impact threshold of <=0.1. Details ▾Hide ▴
Reasoning

The variant is a missense substitution, and the ATM VCEP BP4 rule includes a splicing path for missense variants. That path assigns BP4 Supporting for no predicted splice impact via SpliceAI <=0.1. The observed SpliceAI maximum delta score is 0.023, which is below 0.1. The missense REVEL value of 0.901 does not meet the separate BP4 missense cutoff of <=0.249, so BP4 is assigned only from the VCEP-named splicing prediction and is not double-counted with the PP3 REVEL prediction.

VCEP rule
* Missense: REVEL score **\≤.249** * Splicing: No predicted impact via splicing (SpliceAI **\≤0.1**).
Evidence considered
  • ATM VCEP v1.6 BP4 rule: Missense: REVEL <=.249; Splicing: No predicted impact via splicing (SpliceAI <=0.1).
  • SpliceAI result for NM_000051.4:c.4850T>C: DS_AG 0.000, DS_AL 0.023, DS_DG 0.001, DS_DL 0.023; max delta score 0.023.
  • Local REVEL lookup for NM_000051.4:c.4850T>C: REVEL score 0.901, which does not satisfy the separate BP4 missense cutoff <=0.249; therefore BP4 is based only on the named splicing path.
  • Sun et al. 2025 Supplementary Table S1, exact row ATM c.4850T>C / L1617P: REVEL 0.901 and computational corroboration values; this row does not alter the VCEP BP4 splice threshold or replace the SpliceAI result.
Sources
cspec ↗spliceai ↗revelvcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP7 N/ANot applicable: BP7 is restricted by the ATM VCEP to synonymous and deep intronic variants, not missense substitutions. Details ▾Hide ▴
Reasoning

The variant is missense. The ATM VCEP BP7 applicability statement limits BP7 to synonymous and deep intronic variants, and the RNA path likewise addresses silent substitutions and intronic variants. Therefore BP7 is not applicable regardless of the available SpliceAI result.

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
  • ATM VCEP v1.6 BP7 rule: BP7 is 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) concerns silent substitutions and intronic variants.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.901. BayesDel score = 0.32131.

8 paper records listed. 2 cited in the classification.

Cited in the classification

  • Classical ataxia telangiectasia patients have a congenitally aged immune system with high expression of CD95.
    Carney EF et al. · 2012 Jul 1
    The exact ATM variant c.4850T>C; p.(Leu1617Pro), corresponding to NP_000042.3:p.(L1617P), was reported in patient AT 6 with a second ATM frameshift allele, c.6916delAG; p.2306fs. No residual ATM protein was detected and no residual ATM activity was measured in this patient; the paper does not establish that the missense allele itself is a null variant.
    → PS3 · supporting Names this variant
    PMID 22649200 ↗
    Source detail
    AT 6 ... 14 y, 11 mo ... Male ... 0 ... No ... c.6916delAG; p.2306fs ... c.4850T . C; p.(Leu1617Pro)

    Location Table I, patient AT 6

    Context The study included 15 classical ataxia-telangiectasia patients; ATM mutations were confirmed by sequencing, residual ATM protein was assessed by Western blot, and ATM activity was reported as absent for the cohort.

  • Functional assessment of all ATM SNVs using prime editing and deep learning.
    Lee KS et al. · 2025 Sep 4
    Sun et al. 2025 Supplementary Table S1 contains the exact ATM c.4850T>C / L1617P row. It reports REVEL 0.901, Classification Non-functional, Confidence High, and DeepATM_predicted No. For this computational-evidence group, the REVEL value is corroborative of the independently retrieved REVEL result; the table's functional classification is not used as a substitute for the VCEP predictor-specific PP3 or BP4 rules.
    → PS3 · supporting → PP3 · supporting → BP4 · supporting Names this variant
    PMID 40580951 ↗
    Source detail
    108295000 T C c.4850T>C L1617P exon_32 11 Missense 1617 24.9 0.24891515 0.718682611703698 0.901 0.9938 6.84147080675992e-07 Uncertain significance -2.40621968220889 Non-functional High No

    Location Supplementary Table S1 converted full text, exact row for c.4850T>C

    Context Table S1 from a study assessing ATM single-nucleotide variants using prime editing and deep learning; the exact row identifies the variant as a missense substitution and reports computational predictor fields plus Classification, Confidence, and DeepATM_predicted values.

Other recorded publications

  • Longitudinal analysis of the neurological features of ataxia-telangiectasia.
    Jackson TJ et al. · 2016
    This retrospective longitudinal study of 125 patients with ataxia-telangiectasia examined ATM protein expression, kinase activity, and neurological progression, but did not mention ATM c.4850T>C or p.(Leu1617Pro) and did not provide variant-specific PS4 evidence.
    Does not name this variant
    PMID 26896183 ↗
    Quoted passage
    Consistent with previous reports, we found that the disease is, in general, progressive and that the presence of ATM kinase activity is associated with a milder phenotype.

    Discussion, paragraph 3

  • Hereditary Ataxia Overview.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301317 ↗
  • Ataxia-Telangiectasia.
    Adam MP et al. · 1993
    No paper-specific finding is recorded.
    PMID 20301790 ↗
  • EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood.
    van de Warrenburg BP et al. · 2014
    This EFNS/ENS consensus guideline mentions ataxia-telangiectasia as a diagnostic consideration but does not report ATM c.4850T>C or p.(Leu1617Pro), variant-specific cases, controls, or case-control statistics.
    Does not name this variant
    PMID 24418350 ↗
    Quoted passage
    if there is concomitant chorea plus a severe disturbance of saccades, disorders like ataxia telangiectasia or ataxia with oculomotor apraxia type 2 (AOA2) need to be tested for first.

    Recessive family history, diagnostic work-up discussion

  • 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
    This general ACMG/NSGC practice guideline addresses referral indications for cancer predisposition assessment and provides no variant-specific ATM c.4850T>C or p.(Leu1617Pro) case, control, phenotype-specific, or case-control evidence.
    Does not name this variant
    PMID 25394175 ↗
  • EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias.
    Gasser T et al. · 2010
    No paper-specific finding is recorded.
    PMID 20050888 ↗

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

gnomAD v4.1 1 / 1,614,018 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.023 Open source ↗
ClinVar 1 Uncertain significance · 1 Likely 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= 6.19572e-07; MAF= 0.00006%, 1/1614018 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47511e-07; MAF= 0.00008%, 1/1179926 alleles, homozygotes = 0).

gnomAD v2.1

Absent from gnomAD v2.1.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory) and as Uncertain Significance by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 1018946)

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.901. BayesDel score = 0.32131.

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.