0%
ATMc.7271T>GLikely pathogenic
Print report
Variant interpretation report

ATM c.7271T>G, p.Val2424Gly

NM_000051.4:c.7271T>G NP_000042.3:p.(Val2424Gly) Missense · exon 49 View identifiers
Classification
Likely pathogenic

Variant description:

The ATM NM_000051.4:c.7271T>G (NP_000042.3:p.(Val2424Gly)) missense variant has previously been reported in somatic cancers (COSMIC; COSV53730548, n = 5 times). Experimental evidence: The variant showed no detectable ATM/SMC1 kinase activity and radiosensitivity in the approved Mitui assay, satisfying both VCEP functional-defect requirements. Based on available guidelines, this variant is considered to be Likely 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 3023).

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

Likely pathogenic.A likely 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
PS3Moderate
PS3 · moderate

Met at Moderate: the variant showed no detectable ATM/SMC1 kinase activity and radiosensitivity in the approved Mitui assay, satisfying both VCEP functional-defect requirements.

PM3Moderate
PM3 · moderate

Met at Moderate: one homozygous A-T patient contributes 2.0 VCEP PM3 points, exactly the threshold for PM3 Moderate.

PP3Supporting
PP3 · supporting

Met: REVEL 0.855 exceeds the ATM VCEP PP3 missense threshold of >0.7333, and SpliceAI max delta 0.853 also exceeds ≥0.2.

PP5Supporting
PP5 · supporting

Not applicable: the VCEP explicitly prohibits PP5 under the ClinGen SVI VCEP Review Committee recommendation.

Benign criteria applied · 0

No benign criterion marked as applied in the recorded assessment.

Recorded classification: Likely pathogenic

Likely Pathogenic: PS3 and PM3 at Moderate plus PP3 and PP5 at Supporting satisfy the ATM VCEP Version 1.6 Rule14 combination.

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
104 / 1,613,824 alleles

gnomAD v4.1: 104 / 1,613,824 alleles. Recorded AF 6.44432e-05. Recorded homozygote count 0.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.24998e-05; MAF= 0.00425%, 12/282354 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.53679e-05; MAF= 0.00854%, 11/128854 alleles, homozygotes = 0); grpmax FAF= 4.124e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

No listed criterion applied
gnomAD v4.1 ↗gnomAD v2.1 ↗gnomAD-Canada ↗
No screenshot for this evidence
REVEL score
0.855 recorded score

Recorded REVEL score: 0.855. Refer to the recorded PP3/BP4 rationale for interpretation.

Applied · PP3 →
ClinVar submissions
34 reported laboratory submissions

31 Pathogenic · 2 pathogenic · 1 Likely 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: Loss-of-function; curated oncogenicity label: Likely Oncogenic.

Applied · PS3 → OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
5 recorded samples

This variant has previously been reported in somatic cancers (COSMIC; COSV53730548, n = 5 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 · 7 not met · 2 not assessed · 15 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, PM4, and BP3 are not applicable under the ATM VCEP v1.6 rules because this is a missense substitution, not a null variant, stop-loss variant, or in-frame insertion/deletion in a repetitive region.

Validated functional evidence is concordant for loss of ATM function: the variant fails ATM-specific kinase readouts and radiosensitivity rescue, while the direct prime-editing table classifies it as Non-functional.

The VCEP caps PS3 at Moderate for failure of both ATM-specific function and radiosensitivity and does not support BS3 rescue evidence.

Only PS4 was evidence-evaluable; it was not met because the directly verified case-control comparison had P=0.1, while PP4, PP5, BP5, and BP6 are explicitly not applicable under the ATM VCEP.

PP3 is met at Supporting strength because both VCEP-named computational paths exceed their pathogenic thresholds: REVEL 0.855 > 0.7333 and SpliceAI maximum delta 0.853 ≥ 0.2.

BP4 is not met because neither VCEP benign threshold is satisfied: REVEL 0.855 > 0.249 and SpliceAI maximum delta 0.853 > 0.1.

BP7 is not applicable because the variant is missense rather than synonymous or qualifying deep intronic.

Met · 4

PS3 ModerateVCEPMet at Moderate: the variant showed no detectable ATM/SMC1 kinase activity and radiosensitivity in the approved Mitui assay, satisfying both VCEP functional-defect requirements. Details ▾Hide ▴
Reasoning

PS3 is met at Moderate strength under the ATM VCEP because the variant fails to rescue both an ATM-specific feature and radiosensitivity. In the approved Mitui et al. functional assay (PMID:18634022), ATM c.7271T>G (V2424G) expressed at normal protein levels but had no detectable ATM or SMC1 kinase activity and remained radiosensitive. The approved Scott et al. study (PMID:11830610) independently reported markedly reduced kinase activity for T7271G/Val2424Gly in carrier lymphoblastoid cells. Sun et al. 2025 Supplementary Table S1 independently reports the exact row c.7271T>G / V2424G as Classification=Non-functional, Confidence=High, DeepATM_predicted=No, which is a direct prime-editing measurement and supports PS3_Supporting. The approved assay evidence is concordant with the S1 result, so the maximum applicable VCEP strength is Moderate from the combined ATM-specific kinase defect and radiosensitivity readouts; the VCEP does not allow Strong PS3.

VCEP rule
Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC PS3 rule: a variant failing both an ATM-specific feature and radiosensitivity may receive PS3 Moderate; PS3 Strong is explicitly disallowed.
  • ClinGen HBOP ATM Supplementary Tables 1 and 2: ATM kinase activity is an approved assay category, and Mitui 2009 radiosensitivity may be combined with kinase-activity results for the calibrated stronger functional conclusion; radiosensitivity alone is not used.
  • Mitui et al. 2009, PMID:18634022, Results, ATM Protein Expression; ATM Kinase Activity; Colony Survival Assay: c.7271T>G (V2424G) had normal ATM protein levels, no detectable ATM or SMC1 kinase activity, and radiosensitivity after irradiation.
  • Scott et al. 2002, PMID:11830610: T7271G (Val2424Gly) carrier lymphoblastoid cells showed less than 10% of control in-vitro kinase activity and approximately 15%–25% of control activity for p53 and BRCA1 phosphorylation after ionizing radiation.
  • Sun et al. 2025 Supplementary Table S1, exact row c.7271T>G / V2424G: Classification=Non-functional; Confidence=High; DeepATM_predicted=No; the row is a direct prime-editing measurement and the governing file rule assigns PS3_Supporting.
  • The three functional sources are directionally concordant; no approved-assay conflict requiring human review was identified.
Still missing
  • No variant-specific entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx under c.7271T>G, p.Val2424Gly, or p.V2424G; that file is an assay-methodology and strength-calibration table rather than a per-variant results table.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:18634022 ↗PMID:11830610 ↗
PM3 ModerateVCEPMet at Moderate: one homozygous A-T patient contributes 2.0 VCEP PM3 points, exactly the threshold for PM3 Moderate. Details ▾Hide ▴
Reasoning

The governing ATM PM3/BP2 table has no exact pre-assigned entry for c.7271T>G, p.Val2424Gly, or p.V2424G, so the VCEP point table applies. Stewart et al. report the variant in three A-T families and homozygous in one, with an associated mild variant A-T phenotype. This is an affected A-T proband observation in the VCEP homozygous, confident-phenotype path, which assigns 2.0 PM3 points per unrelated proband, capped at two homozygous individuals. The variant is sufficiently rare under the VCEP prerequisite because gnomAD v4.1 grpmax FAF is 6.973e-05 (0.006973%), below 0.01%. Two points meet the VCEP PM3 Moderate threshold.

VCEP rule
Variant under assessment (VUA) must be sufficiently rare (not meeting a benign population evidence code). ... PM3 = **2** points See ATM PM3/BP2 table for approach to assign points per proband.
Evidence considered
  • ATM_PM3_BP2_1.6.pdf, Ataxia Telangiectasia PM3/BP2 table: the Phenotype confident/Homozygous (max 2 individuals) cell assigns 2.0 points per unrelated A-T proband.
  • Stewart et al. 2001 (PMID:11382771), Introduction, paragraph beginning 'In contrast': 'the second ATM mutation ... associated with a mild variant A-T phenotype ... is a T to G transition at position 7271, which has so far been found in three A-T families, and homozygous in one, in the UK.'
  • gnomAD v4.1: variant grpmax FAF = 6.973e-05 (0.006973%), satisfying the VCEP requirement that the variant not exceed 0.01% population frequency.
  • The governing ATM_PM3_BP2_1.6.pdf text was searched for c.7271T>G, p.Val2424Gly, and p.V2424G; no exact variant row or pre-assigned code was present.
Still missing
  • No exact c.7271T>G, p.Val2424Gly, or p.V2424G entry was found in ATM_PM3_BP2_1.6.pdf.txt; the VCEP point table was therefore applied to the reported homozygous A-T observation.
Sources
vcep_atm_pm3_bp2_1_6 ↗cspec ↗PMID:11382771 ↗gnomad_v4 ↗
PP3 SupportingVCEPMet: REVEL 0.855 exceeds the ATM VCEP PP3 missense threshold of >0.7333, and SpliceAI max delta 0.853 also exceeds ≥0.2. Details ▾Hide ▴
Reasoning

This is a missense variant, so the ATM VCEP PP3 missense path applies. REVEL is 0.855, exceeding the VCEP cutoff of >0.7333. The VCEP also permits the splicing path for missense variants: SpliceAI maximum delta is 0.853, exceeding the cutoff of ≥0.2. Either named predictor path supports PP3; the two predictions are not assigned as separate PP3 evidence items. The exact row in Sun et al. 2025 Supplementary Table S1 for c.7271T>G (V2424G) reports REVEL 0.855 and identifies the variant as Non-functional with High confidence and DeepATM_predicted=No; the row is corroborative for the computational result, while the PP3 decision is based on the VCEP-named REVEL and SpliceAI thresholds.

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
  • Local REVEL predictor lookup for NM_000051.4:c.7271T>G: REVEL score 0.855.
  • SpliceAI lookup for NM_000051.4:c.7271T>G: DS_AG 0.08, DS_AL 0.0, DS_DG 0.036, DS_DL 0.853; maximum delta score 0.853.
  • Sun et al. 2025 Supplementary Table S1, row ATM c.7271T>G / V2424G: REVEL 0.855, Classification=Non-functional, Confidence=High, DeepATM_predicted=No.
  • The exact variant search in Suppl_TableS1_PMID 40580951.xlsx.txt found c.7271T>G at the row reported above; searches for p.Val2424Gly and p.V2424G found no additional matching row in the converted fulltext file.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
PP5 SupportingVCEPNot applicable: the VCEP explicitly prohibits PP5 under the ClinGen SVI VCEP Review Committee recommendation. 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 state that 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 · 7 · evaluated, threshold not reached

PS1 VCEPNot met: the ATM PS1 file has no matching pre-assigned entry, and SpliceAI max delta 0.853 does not rule out splicing. Details ▾Hide ▴
Reasoning

ATM c.7271T>G (p.Val2424Gly/p.V2424G) is a missense variant. The governing ATM PS1 file was searched for all three supplied notations; it contains no entry for this variant or a pre-assigned same-amino-acid PS1 code. The ATM PS1 rule permits missense PS1 only when a splice defect is ruled out for both alterations, but the case evidence reports SpliceAI max delta 0.853, so that prerequisite is not satisfied. Therefore PS1 is not met.

VCEP rule
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.txt was searched for c.7271T>G, p.Val2424Gly, and p.V2424G; no matching variant entry or pre-assigned PS1 code was found.
  • The case SpliceAI result is max delta 0.853 (DS_DL 0.853), so a splice defect is not ruled out for the missense variant.
  • The ATM PS1 guide states that missense PS1 may be applied only when a splice defect is ruled out for both alterations.
Still missing
  • No entry for c.7271T>G, p.Val2424Gly, or p.V2424G was found in ATM_PS1_1.6.pdf.txt.
Sources
vcep_atm_ps1_1_6 ↗spliceai ↗
PS4 VCEPNot met: the directly reported case-control comparison was 7/3,743 versus 0/1,268, with P=0.1, and the continuity-corrected OR 5.09 had 95% CI 0.29–89.23. Details ▾Hide ▴
Reasoning

The VCEP 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. The directly verified Bernstein et al. study (PMID:16958054) reports 7/3,743 breast-cancer cases versus 0/1,268 controls for c.7271T>G, P=0.1. Treating the zero-control cell with the Haldane-Anscombe 0.5 correction, I computed OR=(7.5×1268.5)/(3736.5×0.5)=5.0923 and 95% CI 0.2906–89.2291; the reported p-value fails the VCEP p-value requirement and the CI includes 1. The directly verified Chenevix-Trench et al. study (PMID:11830610) reports one case and no controls, but provides no qualifying p-value or variant-specific case-control effect estimate. The directly verified Tavtigian et al. study (PMID:21787400) reports a variant-specific 8.0-fold risk estimate (95% CI 2.3–27.4; P=0.0005) for 15 carrier families, but this is family-based penetrance/segregation analysis rather than the VCEP-required case-control comparison. The literature packet also contains an AI-classified lead for PMID:27595995 reporting OR 11.0, but no source-registry entry or fetched full text was available to independently verify it, so it was not used as 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 PS4 rule: case-control studies require p-value ≤.05 and (odds ratio, hazard ratio, or relative risk ≥2 or lower 95% CI ≥1.5).
  • Bernstein et al. 2006, PMID:16958054, abstract lines 19–24: 7/3,743 cases and 0/1,268 controls carried c.7271T4G; reported P=0.1 and HR=8.6 (95% CI 3.9–18.9) for cumulative-risk penetrance, not a qualifying case-control p-value/effect pair.
  • From the PMID:16958054 counts, I computed the case-control OR with Haldane-Anscombe correction: OR=5.0923; 95% CI=0.2906–89.2291.
  • Chenevix-Trench et al. 2002, PMID:11830610, abstract: one T7271G carrier among 525 case patients and none among 381 controls; no variant-specific p-value or qualifying case-control effect estimate was reported in the extracted evidence.
  • Tavtigian et al. 2011, PMID:21787400, Results: 15 c.7271T>G carrier families had an 8.0-fold breast-cancer risk estimate (95% CI 2.3–27.4; P=0.0005), but this was family-based penetrance analysis, not the required case-control comparison.
  • The literature-pass AI lead for PMID:27595995 states OR=11.0 for c.7271T>G, but the paper could not be independently verified from a source-registry-linked full text and was not used.
Still missing
  • Independent verification of the PMID:27595995 variant-specific OR 11.0 lead is unavailable because that paper has no source_registry entry or fetched full text in this case.
Sources
cspec ↗PMID:16958054 ↗PMID:11830610 ↗PMID:21787400 ↗
PM2 VCEPNot met: the highest gnomAD subpopulation AF is 0.0083059% (98 alleles), exceeding the VCEP PM2 threshold of ≤0.001%. Details ▾Hide ▴
Reasoning

The ATM VCEP PM2 Supporting threshold is frequency ≤0.001% in the gnomAD subpopulation with the highest frequency, with an exception only for a singleton confined to one subpopulation. The highest observed subpopulation frequency is 0.0083059% in gnomAD v4.1 European (non-Finnish), based on 98 alleles, and 0.00853679% in gnomAD v2.1 European (non-Finnish), based on 11 alleles; neither qualifies and neither is the singleton exception, so PM2 is not met.

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
  • ClinGen HBOP ATM VCEP v1.6 CSPEC PM2 rule: Frequency ≤.001% in the gnomAD subpopulation with the highest frequency; the exception requires >0.001% but n=1 in a single subpopulation and absence from every other subpopulation.
  • gnomAD v4.1: highest subpopulation is European (non-Finnish), AF = 8.305901e-05 (0.0083059%), 98/1,179,884 alleles, homozygotes = 0.
  • gnomAD v2.1: highest subpopulation is European (non-Finnish), AF = 8.536794e-05 (0.00853679%), 11/128,854 alleles, homozygotes = 0.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BA1 VCEPNot met: gnomAD v4.1 grpmax filtering AF is 0.006973%, below the VCEP BA1 threshold of >0.5%. Details ▾Hide ▴
Reasoning

The ATM VCEP BA1 threshold is a grpmax filtering allele frequency greater than 0.5% in gnomAD. The observed grpmax filtering AF is 0.006973% in gnomAD v4.1 and 0.004124% in gnomAD v2.1, both far below the threshold; therefore BA1 is not met.

VCEP rule
Grpmax Filtering AF **\>.5%** in gnomAD
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC BA1 rule: Grpmax Filtering AF >.5% in gnomAD.
  • gnomAD v4.1: grpmax filtering AF = 6.973e-05 (0.006973%), total AF = 6.444321e-05, 104/1,613,824 alleles, homozygotes = 0.
  • gnomAD v2.1: grpmax filtering AF = 4.124e-05 (0.004124%), total AF = 4.249984e-05, 12/282,354 alleles, homozygotes = 0.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BS1 VCEPNot met: gnomAD v4.1 grpmax filtering AF is 0.006973%, below the VCEP BS1 threshold of >0.05%. Details ▾Hide ▴
Reasoning

The ATM VCEP BS1 threshold is a grpmax filtering allele frequency greater than 0.05% in gnomAD. The observed grpmax filtering AF is 0.006973% in gnomAD v4.1 and 0.004124% in gnomAD v2.1, both below the threshold; therefore BS1 is not met.

VCEP rule
Grpmax Filtering AF **\>.05%** in gnomAD
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC BS1 rule: Grpmax Filtering AF >.05% in gnomAD.
  • gnomAD v4.1: grpmax filtering AF = 6.973e-05 (0.006973%), total AF = 6.444321e-05, 104/1,613,824 alleles, homozygotes = 0.
  • gnomAD v2.1: grpmax filtering AF = 4.124e-05 (0.004124%), total AF = 4.249984e-05, 12/282,354 alleles, homozygotes = 0.
Sources
cspec ↗gnomad_v4 ↗gnomad_v2 ↗
BS3 VCEPNot met: approved assays showed no ATM/SMC1 kinase rescue and persistent radiosensitivity, while the direct prime-editing row classified c.7271T>G as Non-functional. Details ▾Hide ▴
Reasoning

BS3 is not met because the available validated functional assays show loss rather than rescue of ATM function. In the approved Mitui et al. assay (PMID:18634022), c.7271T>G (V2424G) had no detectable ATM or SMC1 kinase activity and remained radiosensitive despite normal ATM protein expression. The approved Scott et al. study (PMID:11830610) likewise reported markedly reduced kinase and ATM-target phosphorylation activity. Sun et al. 2025 Supplementary Table S1 reports the exact variant as directly measured Non-functional with High confidence and DeepATM_predicted=No, which supports PS3 rather than BS3. Therefore neither the VCEP BS3 Supporting rescue condition nor the BS3 Moderate condition is satisfied.

VCEP rule
Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity. ... 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; BS3 Moderate requires rescue of both.
  • Mitui et al. 2009, PMID:18634022, Results, ATM Kinase Activity and Colony Survival Assay: the c.7271T>G construct had no detectable kinase activity and was radiosensitive.
  • Scott et al. 2002, PMID:11830610: T7271G/Val2424Gly carrier cells had markedly reduced kinase activity and reduced phosphorylation of ATM targets.
  • Sun et al. 2025 Supplementary Table S1, exact row c.7271T>G / V2424G: Classification=Non-functional; Confidence=High; DeepATM_predicted=No.
Still missing
  • No variant-specific entry was found in clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx under c.7271T>G, p.Val2424Gly, or p.V2424G; that file is an assay-methodology and strength-calibration table rather than a per-variant results table.
Sources
cspec ↗vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:18634022 ↗PMID:11830610 ↗
BP4 VCEPNot met: REVEL 0.855 is above the BP4 missense cutoff of ≤0.249, while SpliceAI max delta 0.853 is above the no-impact cutoff of ≤0.1. Details ▾Hide ▴
Reasoning

This is a missense variant, for which the ATM VCEP BP4 rule names REVEL ≤0.249; the observed REVEL score is 0.855, so the missense path is not met. The VCEP also lists a splicing path requiring no predicted impact with SpliceAI ≤0.1; the observed maximum delta score is 0.853, so that path is not met either. The same prediction is not counted as separate benign evidence, and BP4 is not applied.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • Local REVEL predictor lookup for NM_000051.4:c.7271T>G: REVEL score 0.855, above the VCEP BP4 missense cutoff.
  • SpliceAI lookup for NM_000051.4:c.7271T>G: maximum delta score 0.853, above the VCEP BP4 no-predicted-impact cutoff.
Sources
cspec ↗revelspliceai ↗

Not assessed · 2 · no assessment recorded

PP1 VCEPNot assessed: reported segregation is in AD breast-cancer families, while qualifying AR segregation of both variants in an affected relative is not documented. Details ▾Hide ▴
Reasoning

The ATM VCEP permits PP1 only on its AR path, with strength based on segregation in affected relatives; affected relatives must have both variants identified in the proband. The available variant-specific family reports concern breast-cancer families, an AD context that the VCEP says not to use for PP1, while the cited A-T family information does not document sufficient qualifying segregation and phase for an affected relative. Therefore the AR PP1 rule cannot be evaluated.

VCEP rule
* AR Condition: Affected relatives must have both variants identified in proband. * AD Condition – Do not use: Co-segregation analysis in lower-penetrance genes can lead to false positive results (PMID 32773770) ... AR Condition: Segregation in 1 affected relative
Evidence considered
  • ATM VCEP v1.6 PP1 rule: supporting strength requires segregation in 1 affected relative, with stronger strengths requiring 2 or at least 3 affected relatives.
  • ATM VCEP v1.6 PP1 instructions require affected relatives to have both variants identified in the proband and state not to use the AD condition.
  • Chenevix-Trench et al. 2002, PMID:11830610, Results: in breast-cancer family A, all breast-cancer patients carried T7271G, but five unaffected carriers were also identified; this is AD breast-cancer segregation and is not the VCEP's usable AR PP1 path.
  • Thompson et al. 2011, PMID:21787400, family analysis: 15 families carrying ATM c.7271T>G were analyzed for breast-cancer risk; this is AD breast-cancer family evidence, not documented AR A-T segregation with both variants in affected relatives.
Still missing
  • A qualifying AR A-T pedigree documenting both variants in the proband and segregation of both variants in at least one affected relative is not available.
Sources
cspec ↗PMID:11830610 ↗PMID:21787400 ↗
BP2 VCEPNot assessed: no qualifying unaffected adult in-trans observation or cis pathogenic-variant phase is documented for BP2. Details ▾Hide ▴
Reasoning

The ATM VCEP BP2 rule requires observation in cis with a pathogenic variant or, for the relevant unaffected-person downgrade path, an unaffected adult with the variant in trans with a pathogenic or likely pathogenic ATM variant. The available evidence reports affected A-T families and a homozygous occurrence of c.7271T>G, but does not document a qualifying unaffected adult in-trans observation or a cis pathogenic-variant phase observation. Therefore no BP2 points can be assigned.

VCEP rule
BP2 requires an applicable cis or qualifying unaffected-adult in-trans observation; no points are assigned because that evidence is not documented.
Evidence considered
  • ATM_PM3_BP2_1.6.pdf defines BP2 as 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, and its downgrade note specifies an unaffected adult over 18 years with no evidence of A-T for an in-trans or homozygous observation.
  • Stewart et al. 2001 (PMID:11382771) reports affected A-T families and one homozygous occurrence, but does not establish the qualifying unaffected-adult in-trans or cis observation required for BP2.
  • The governing ATM_PM3_BP2_1.6.pdf text was searched for c.7271T>G, p.Val2424Gly, and p.V2424G; no exact variant row or pre-assigned code was present.
Still missing
  • No exact c.7271T>G, p.Val2424Gly, or p.V2424G entry was found in ATM_PM3_BP2_1.6.pdf.txt.
  • No documented unaffected adult aged over 18 years with c.7271T>G in trans with a pathogenic or likely pathogenic ATM variant was identified.
  • No documented cis phase observation with a pathogenic variant was identified.
Sources
vcep_atm_pm3_bp2_1_6 ↗cspec ↗PMID:11382771 ↗
Not applicable · 15· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANot applicable: c.7271T>G is a missense substitution, whereas ATM PVS1 is restricted to null variants such as nonsense, frameshift, splice-site, and exon-deletion changes. Details ▾Hide ▴
Reasoning

The queried variant is NM_000051.4:c.7271T>G, p.(Val2424Gly), a missense substitution in coding exon 49, not a nonsense, frameshift, canonical splice-site, initiation-codon, or single-/multi-exon deletion variant. The ATM VCEP PVS1 definition is restricted to null variants, so the PVS1 decision tree does not apply. The governing ATM_PVS1_1.6.pdf was searched for c.7271T>G, p.Val2424Gly, and p.V2424G; no exact entry was found.

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
Evidence considered
  • Case normalization identifies NM_000051.4:c.7271T>G as NP_000042.3:p.(Val2424Gly), a missense variant.
  • ATM_PVS1_1.6.pdf defines PVS1 for null variants: nonsense, frameshift, canonical +/-1 or 2 splice sites, initiation codon, or single-/multi-exon deletion.
  • ATM_PVS1_1.6.pdf.txt was searched for c.7271T>G, p.Val2424Gly, and p.V2424G; no exact variant entry was found.
Still missing
  • No exact c.7271T>G, p.Val2424Gly, or p.V2424G entry was found in ATM_PVS1_1.6.pdf.txt.
Sources
cspec ↗vcep_atm_pvs1_1_6 ↗
PS2 VCEPNot applicable: the ATM VCEP prohibits PS2 for both AD and AR disease because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

The ATM VCEP instructs that PS2 is not used for either autosomal-dominant or autosomal-recessive disease because informative de novo occurrences have not been observed and de novo recessive disease is unlikely to be informed by phase. The variant is assessed under ATM hereditary cancer and ataxia-telangiectasia contexts, so no PS2 evidence is assigned.

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
  • ATM VCEP v1.6 PS2 instructions: de novo evidence is not used for AD or AR disease because informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
Sources
cspec ↗
PM1 VCEPNot applicable: the ATM VCEP explicitly marks PM1 Not Applicable, with no authoritative ATM domain-table entry available. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC entry marks PM1 as Not Applicable. The consolidated vcep_materials.json also has no domain_tables entry for ATM; no alternate domain route may be substituted for the VCEP's explicit applicability decision.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC criteria entry for PM1: applicability = Not Applicable.
  • vcep_materials.json domain_tables is empty for ATM.
Sources
cspec ↗
PM4 N/ANot applicable: p.(Val2424Gly) is a missense substitution with no protein-length change, while the ATM VCEP PM4 rule applies only to stop-loss variants. Details ▾Hide ▴
Reasoning

The queried variant is a missense substitution, p.(Val2424Gly), with no protein-length change. The ATM VCEP PM4 rule is limited to stop-loss variants; therefore PM4 does not apply to this missense change.

VCEP rule
Use for stop-loss variants.
Evidence considered
  • Case normalization identifies NP_000042.3:p.(Val2424Gly), a missense substitution that does not alter protein length.
  • The ATM VCEP PM4 instructions state: Use for stop-loss variants, only.
Sources
cspec ↗
PM5 N/ANot applicable: PM5 is limited to NMD-prone truncating variants with Very Strong PVS1, whereas this variant is missense p.Val2424Gly. Details ▾Hide ▴
Reasoning

The ATM VCEP PM5 rule is restricted to NMD-prone truncating DNA or observed NMD-prone truncating splice variants receiving PVS1 or PVS1(RNA) at Very Strong, with premature termination codons upstream of p.Leu3048. This variant is a missense substitution at p.Val2424Gly, so it is outside the rule's stated variant types.

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 CSPEC PM5 rule limits application to NMD-prone truncating DNA or observed NMD-prone truncating splice variants with Very Strong PVS1/PVS1(RNA) and termination codons upstream of p.Leu3048.
  • The case normalization identifies NM_000051.4:c.7271T>G as NP_000042.3:p.(Val2424Gly), a missense change.
Sources
cspec ↗
PM6 VCEPNot applicable: the ATM VCEP prohibits PM6 for both AD and AR disease because informative de novo occurrences have not been observed. Details ▾Hide ▴
Reasoning

The ATM VCEP instructs that PM6 is not used for either autosomal-dominant or autosomal-recessive disease because informative de novo occurrences have not been observed and de novo recessive disease is unlikely to be informed by phase. No PM6 evidence is therefore assignable.

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
  • ATM VCEP v1.6 PM6 instructions: de novo evidence is not used for AD or AR disease because informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.
Sources
cspec ↗
PP2 VCEPNot applicable: the ATM VCEP explicitly marks PP2 Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC entry explicitly marks PP2 as Not Applicable.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC criteria entry for PP2: applicability = Not Applicable.
Sources
cspec ↗
PP4 VCEPNot applicable: the VCEP prohibits PP4 for both ATM-related breast cancer and autosomal-recessive ataxia-telangiectasia. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP marks PP4 not applicable. Its instructions prohibit PP4 for autosomal-dominant ATM-related breast cancer because breast cancer has multiple genetic etiologies and no readily distinguishing phenotype, and prohibit it as a separate line for autosomal-recessive ataxia-telangiectasia because the 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 applicability instructions: autosomal-dominant PP4 is prohibited for breast cancer, and autosomal-recessive PP4 is not used separately because it is incorporated into PM3/BP2.
Sources
cspec ↗
BS2 VCEPNot applicable: the ATM VCEP excludes BS2 because ATM has incomplete penetrance. Details ▾Hide ▴
Reasoning

The ATM VCEP marks BS2 not applicable because ATM has incomplete penetrance; absence of disease in a healthy adult cannot be used for this criterion.

VCEP rule
Do not use: ATM has incomplete penetrance.
Evidence considered
  • ClinGen HBOP ATM VCEP v1.6 CSPEC BS2 applicability instruction: Do not use: ATM has incomplete penetrance.
Sources
cspec ↗
BS4 VCEPNot applicable: the ATM VCEP assigns no weight to informative lack of co-segregation in ataxia-telangiectasia families. Details ▾Hide ▴
Reasoning

The ATM VCEP states that informative instances of lack of co-segregation in ataxia-telangiectasia families are too rare to receive weight at this time; such observations may instead be considered for BP2 when biallelic unaffected patients are observed. BS4 is therefore not applicable here.

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
  • ATM VCEP v1.6 BS4 instructions: informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and may be considered for BP2 if biallelic unaffected patients are observed.
Sources
cspec ↗
BP1 VCEPNot applicable: the ATM VCEP explicitly marks BP1 Not Applicable for this framework. Details ▾Hide ▴
Reasoning

The ATM VCEP CSPEC entry explicitly marks BP1 as Not Applicable.

VCEP rule
Not Applicable
Evidence considered
  • ATM VCEP CSPEC entry for BP1: applicability = Not Applicable.
Sources
cspec ↗
BP3 VCEPNot applicable: BP3 is explicitly prohibited by the ATM VCEP and the variant is missense rather than an in-frame deletion or insertion in a repetitive region. Details ▾Hide ▴
Reasoning

The queried variant is a missense substitution rather than an in-frame deletion or insertion. The ATM VCEP explicitly marks BP3 as not applicable and instructs assessors not to use it, so repeat-region context cannot activate BP3 for this variant.

VCEP rule
Do not use.
Evidence considered
  • Case normalization identifies NP_000042.3:p.(Val2424Gly), a missense substitution rather than an in-frame insertion or deletion.
  • The ATM VCEP BP3 entry is marked Not applicable and its instructions state: Do not use.
Sources
cspec ↗
BP5 VCEPNot applicable: the VCEP prohibits BP5 because multiple pathogenic variants can occur without a noticeable phenotype difference in low-penetrance ATM disease. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP explicitly marks BP5 not applicable and instructs that it should not be used because cases with multiple pathogenic variants have been observed without a noticeable phenotype difference and ATM has low penetrance.

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 VCEP explicitly prohibits BP6 under the ClinGen SVI VCEP Review Committee recommendation. Details ▾Hide ▴
Reasoning

The ATM HBOP VCEP explicitly marks BP6 not applicable and states that the criterion is not for use under the ClinGen SVI VCEP Review Committee recommendation.

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 state that this criterion is not for use as recommended by the ClinGen Sequence Variant Interpretation VCEP Review Committee.
Sources
cspec ↗
BP7 N/ANot applicable: c.7271T>G is an exonic missense variant, whereas ATM VCEP BP7 applies to synonymous or qualifying deep intronic variants. Details ▾Hide ▴
Reasoning

BP7 is limited by the ATM VCEP to synonymous and qualifying deep intronic variants, with an RNA-observation path also specified for silent and intronic variants. NM_000051.4:c.7271T>G is an exonic missense variant (p.Val2424Gly), so BP7 is outside its governing scope and no BP7 evidence is evaluated.

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.
Evidence considered
  • Case normalization identifies NM_000051.4:c.7271T>G as NP_000042.3:p.(Val2424Gly), an exonic missense variant.
Sources
cspec ↗

Identifiers

Gene
ATM
Transcript
NM_000051.4
Coding (HGVS c.)
NM_000051.4:c.7271T>G
Protein (HGVS p.)
NP_000042.3:p.(Val2424Gly)
GRCh38
chr11:108329202 T>G
GRCh37
chr11:108199929 T>G
Location and type
Exon 49 · missense
ClinVar
267405, 3023, 481238, 3047
COSMIC
COSV53730548

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 v4.1 104 / 1,613,824 alleles AF 6.44e-05 · 0 homozygotes · FAF 6.97e-05
gnomAD v2.1 12 / 282,354 alleles AF 4.25e-05 · 0 homozygotes · FAF 4.12e-05
gnomAD-Canada v1.0 Allele count data not recorded

By genetic ancestry

gnomAD v4.1

AF 6.4e-05 · 104 / 1,613,824 alleles · 0 hom · FAF 7e-05
European (non-Finnish)98 / 1,179,884 8.3e-05
Remaining individuals4 / 62,466 6.4e-05
Admixed American1 / 60,004 1.7e-05
African/African American1 / 74,926 1.3e-05
0 alternate alleles recorded in 6 other groups: European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.

gnomAD v2.1

AF 4.2e-05 · 12 / 282,354 alleles · 0 hom · FAF 4.1e-05
European (non-Finnish)11 / 128,854 8.5e-05
Admixed American1 / 35,400 2.8e-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= 6.44432e-05; MAF= 0.00644%, 104/1613824 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.3059e-05; MAF= 0.00831%, 98/1179884 alleles, homozygotes = 0); grpmax FAF= 6.973e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.24998e-05; MAF= 0.00425%, 12/282354 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.53679e-05; MAF= 0.00854%, 11/128854 alleles, homozygotes = 0); grpmax FAF= 4.124e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

SpliceAI and Pangolin

SpliceAI acceptor lossat +231 bp
0.000
SpliceAI acceptor gainat -99 bp
0.080
SpliceAI donor lossat -2 bp
0.853
SpliceAI donor gainat +36 bp
0.036
Pangolin splice lossmagnitude shown
-0.551
Pangolin splice gain
0.156

Other predictors

REVEL
0.855
BayesDel
0.332

How the predictions were used

PP3 SupportingVCEPMet: REVEL 0.855 exceeds the ATM VCEP PP3 missense threshold of >0.7333, and SpliceAI max delta 0.853 also exceeds ≥0.2. Details ▾Hide ▴
Reasoning

This is a missense variant, so the ATM VCEP PP3 missense path applies. REVEL is 0.855, exceeding the VCEP cutoff of >0.7333. The VCEP also permits the splicing path for missense variants: SpliceAI maximum delta is 0.853, exceeding the cutoff of ≥0.2. Either named predictor path supports PP3; the two predictions are not assigned as separate PP3 evidence items. The exact row in Sun et al. 2025 Supplementary Table S1 for c.7271T>G (V2424G) reports REVEL 0.855 and identifies the variant as Non-functional with High confidence and DeepATM_predicted=No; the row is corroborative for the computational result, while the PP3 decision is based on the VCEP-named REVEL and SpliceAI thresholds.

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
  • Local REVEL predictor lookup for NM_000051.4:c.7271T>G: REVEL score 0.855.
  • SpliceAI lookup for NM_000051.4:c.7271T>G: DS_AG 0.08, DS_AL 0.0, DS_DG 0.036, DS_DL 0.853; maximum delta score 0.853.
  • Sun et al. 2025 Supplementary Table S1, row ATM c.7271T>G / V2424G: REVEL 0.855, Classification=Non-functional, Confidence=High, DeepATM_predicted=No.
  • The exact variant search in Suppl_TableS1_PMID 40580951.xlsx.txt found c.7271T>G at the row reported above; searches for p.Val2424Gly and p.V2424G found no additional matching row in the converted fulltext file.
Sources
cspec ↗revelspliceai ↗vcep_suppl_tables1_pmid_40580951 ↗PMID:40580951 ↗
BP4 VCEPNot met: REVEL 0.855 is above the BP4 missense cutoff of ≤0.249, while SpliceAI max delta 0.853 is above the no-impact cutoff of ≤0.1. Details ▾Hide ▴
Reasoning

This is a missense variant, for which the ATM VCEP BP4 rule names REVEL ≤0.249; the observed REVEL score is 0.855, so the missense path is not met. The VCEP also lists a splicing path requiring no predicted impact with SpliceAI ≤0.1; the observed maximum delta score is 0.853, so that path is not met either. The same prediction is not counted as separate benign evidence, and BP4 is not applied.

VCEP rule
* Missense: REVEL score **≤.249** * Splicing: No predicted impact via splicing (SpliceAI **≤0.1**).
Evidence considered
  • Local REVEL predictor lookup for NM_000051.4:c.7271T>G: REVEL score 0.855, above the VCEP BP4 missense cutoff.
  • SpliceAI lookup for NM_000051.4:c.7271T>G: maximum delta score 0.853, above the VCEP BP4 no-predicted-impact cutoff.
Sources
cspec ↗revelspliceai ↗
BP7 N/ANot applicable: c.7271T>G is an exonic missense variant, whereas ATM VCEP BP7 applies to synonymous or qualifying deep intronic variants. Details ▾Hide ▴
Reasoning

BP7 is limited by the ATM VCEP to synonymous and qualifying deep intronic variants, with an RNA-observation path also specified for silent and intronic variants. NM_000051.4:c.7271T>G is an exonic missense variant (p.Val2424Gly), so BP7 is outside its governing scope and no BP7 evidence is evaluated.

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.
Evidence considered
  • Case normalization identifies NM_000051.4:c.7271T>G as NP_000042.3:p.(Val2424Gly), an exonic missense variant.
Sources
cspec ↗

Statement

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.85). REVEL score = 0.855. BayesDel score = 0.331717.

8 paper records listed. 3 cited in the classification.

Cited in the classification

  • Residual ataxia telangiectasia mutated protein function in cells from ataxia telangiectasia patients, with 5762ins137 and 7271T-->G mutations, showing a less severe phenotype.
    Stewart GS et al. · 2001 Aug 10
    The paper explicitly studied cells carrying the ATM 7271T>G missense mutation and reported markedly reduced ATM kinase activity of approximately 6% of normal with abnormal ATM-dependent DNA-damage responses.
    → PS3 · moderate → PM3 · moderate Names this variant
    PMID 11382771 ↗
    Source detail
    The mutant ATM kinase activity in the 7271T-->G cells was only about 6% that of the activity in normal cells

    Location Abstract

    Context Patient-derived cells from an ataxia-telangiectasia family with the 7271T>G missense mutation were assessed for ATM-dependent functions and in-vitro kinase activity.

  • Dominant negative ATM mutations in breast cancer families.
    Chenevix-Trench G et al. · 2002 Feb 6
    The paper explicitly reports ATM T7271G/Val2424Gly. In family A, all tested breast-cancer patients carried the variant, but five unaffected carriers were also identified; the paper also refers to the variant in two A-T families without providing a qualifying AR segregation-and-phase dataset for this assessment.
    → PS3 · moderate Names this variant
    PMID 11830610 ↗
    Source detail
    Further genotyping revealed that, in family A, all of the case patients with breast cancer were carriers of the T7271G mutation, as was the woman with gastric cancer (Fig. 1). Five unaffected carriers were also identified in the family.

    Location Results, paragraphs beginning "To estimate the frequency" and "We genotyped"

    Context Australian population-based case-control-family study; genotyping of breast-cancer families; family segregation and penetrance analysis.

  • Functional and computational assessment of missense variants in the ataxia-telangiectasia mutated (ATM) gene: mutations with increased cancer risk.
    The study directly tested ATM c.7271T>G (V2424G) by site-directed mutagenesis of full-length ATM cDNA and stable transfection into ATM-deficient AT7LA lymphoblastoid cells. The variant produced normal ATM protein levels but no detectable ATM or SMC1 kinase activity and radiosensitivity after irradiation.
    → PS3 · moderate Names this variant
    PMID 18634022 ↗
    Source detail
    The c.5858C>T (T1953I) and c.7271T>G (V2424G) constructs showed trace and normal ATM levels, respectively, but no detectable kinase activity, similar to the LCL derived from the c.7271T>G patient that was described by Stewart et al. (2001). ... the exception of transfectant c.7271T>G, which was radiosensitive, despite normal levels of ATM protein; however, the protein has little or no ATM kinase

    Location Results, ATM Kinase Activity; Results, Colony Survival Assay

    Context Full-length ATM cDNA constructs were stably transfected into ATM-deficient AT7LA lymphoblastoid cells; ATM-S1981 autophosphorylation and SMC1 phosphorylation were measured after irradiation, and colony survival was assessed after ionizing radiation.

Other recorded publications

  • Population-based estimates of breast cancer risks associated with ATM gene variants c.7271T>G and c.1066-6T>G (IVS10-6T>G) from the Breast Cancer Family Registry.
    Bernstein JL et al. · 2006
    The paper explicitly reports ATM c.7271T4G/p.Val2424Gly. It found 7 heterozygous carriers among 3,743 breast-cancer cases and 0 among 1,268 controls, with P=0.1 for the case-control comparison. Applying a Haldane-Anscombe 0.5 correction to the zero-control cell gives OR=5.0923 and 95% CI 0.2906–89.2291; the p-value and CI do not satisfy the VCEP PS4 rule.
    Names this variant
    PMID 16958054 ↗
    Quoted passage
    Using population-based blood samples we found that 7 out of 3,743 breast cancer cases (0.2%) and 0 out of 1,268 controls were heterozygous for the c.7271T4G allele (P 5 0.1).

    Abstract, lines 16–24; Results; Table 3

  • Modeling ATM mutant proteins from missense changes confirms retained kinase activity.
    Barone G et al. · 2009
    No paper-specific finding is recorded.
    PMID 19431188 ↗
  • Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.
    No paper-specific finding is recorded.
    PMID 19781682 ↗
  • Rare variants in the ATM gene and risk of breast cancer.
    The paper explicitly studied ATM c.7271T>G/p.Val2424Gly and analyzed 15 variant-carrier families for breast-cancer penetrance, reporting an 8.0-fold increased risk. This is family evidence for the AD breast-cancer context, which the ATM VCEP instructs not to use for PP1.
    Names this variant
    PMID 21787400 ↗
    Quoted passage
    Separate analyses of the 15 families carrying the ATM c.7271T > G variant found that this variant increased breast cancer risk by a factor of 8.0 (95% CI, 2.3 to 27.4; P = 0.0005) compared with 4.4 (95% CI, 0.70 to 28.1; P = 0.053) for families with other variants.

    Results, Penetrance analysis in families

  • Clinical evaluation of a multiple-gene sequencing panel for hereditary cancer risk assessment.
    No paper-specific finding is recorded.
    PMID 24733792 ↗

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

gnomAD v4.1 104 / 1,613,824 recorded alleles Open source ↗
gnomAD v2.1 Captured gnomAD v2.1 source record Open source ↗
SpliceAI Lookup Recorded maximum delta 0.853 Open source ↗
ClinVar 31 Pathogenic · 2 pathogenic · 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= 6.44432e-05; MAF= 0.00644%, 104/1613824 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.3059e-05; MAF= 0.00831%, 98/1179884 alleles, homozygotes = 0); grpmax FAF= 6.973e-05.

gnomAD v2.1

This variant is present in gnomAD v2.1 (AF= 4.24998e-05; MAF= 0.00425%, 12/282354 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.53679e-05; MAF= 0.00854%, 11/128854 alleles, homozygotes = 0); grpmax FAF= 4.124e-05.

gnomAD-Canada

Absent from gnomAD-Canada v1.0.

ClinVar

This variant has been reported in ClinVar as Pathogenic (31 clinical laboratories) and as pathogenic (2 clinical laboratories) and as Likely pathogenic (1 clinical laboratory) and as Pathogenic by ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Variant Curation Expert Panel, ClinGen (expert panel). (ClinVarID = 3023)

In silico

SpliceAI predicts possible splice impact for this variant (max delta score = 0.85). REVEL score = 0.855. BayesDel score = 0.331717.

Functional

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: 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; COSV53730548, n = 5 times).

Cancer Hotspots

This variant does not lie in a statistically significant hotspot.