Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
This variantScenario
BenignPathogenic
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
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.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is ClinGen ATM VCEP v1.5. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
No pathogenic criterion marked as applied in the recorded assessment.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
No criterion meets the governing ATM VCEP v1.5 thresholds (closest: REVEL 0.733 vs 0.7333), so the classification is Uncertain Significance.
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
631 / 1,613,474 alleles
gnomAD v4.1: 631 / 1,613,474 alleles. Recorded AF 0.000391082. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000304675; MAF= 0.03047%, 86/282268 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000605496; MAF= 0.06055%, 78/128820 alleles, homozygotes = 0); grpmax FAF= 0.00053252.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0002171788467803236, 4/18418 alleles, homozygotes = 0).
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.
ACMG/AMP criteria under ClinGen ATM VCEP v1.5, with the data and sources behind each one.
28 criteria with recorded statuses: 0 met · 7 not met · 7 not assessed · 14 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
NM_000051.4:c.4324T>C / NP_000042.3:p.(Tyr1442His) is a single-nucleotide missense substitution: no frameshift, no premature stop, no canonical splice disruption, no exon deletion, no stop-loss, and no in-frame indel or repeat-region change.
Under the ATM VCEP v1.5 CSPEC (governing framework for this gene, taking precedence over generic ACMG), PVS1's decision tree is scoped to null variants only, PM4 is scoped to stop-loss variants only, and BP3 is explicitly disabled (Not Applicable) - none of these gates are met or entered by a missense substitution, so all three criteria in this group are not_applicable rather than not_met.
ATM VCEP v1.5 (governing CSPEC) explicitly designates PM1, PP2, and BP1 as 'Not Applicable' for this gene, so all three are set not_applicable rather than assessed under generic ACMG logic.
ATM VCEP v1.5 defines PM5 only as a truncation-cutoff rule for frameshift/truncating/NMD-prone splice variants upstream of p.Arg3047, with no missense same-residue comparator sub-path; since NM_000051.4:c.4324T>C is missense, PM5 is not applicable, consistent with the case's own pm5_candidates artifact (eligible_for_classic_pm5_search=false).
PS1 under the ATM VCEP v1.5 missense sub-path requires an established P/LP variant sharing the same amino acid change p.(Tyr1442His) with splicing ruled out for both; no such comparator variant was identified in the available evidence bundle, and the variant's own ClinVar record is itself a VUS, so PS1 is left not_assessed pending a dedicated comparator search rather than defaulted to not_met.
For the ATM VCEP v1.5 framework, PS2, PM6, and BS4 are not applicable.
PP1 is applicable in principle under the ATM VCEP AR segregation rule, but the case bundle contains no variant-specific segregation, parental, pedigree, meiosis, or non-segregation data; PP1 is therefore not assessed.
ATM VCEP v1.5 requires PS3/BS3 to be grounded in one of three specific approved functional-assay papers (kinase activity: Mitui 2009/PMID 18634022, Barone 2009/PMID 19431188, Scott 2002/PMID 11805335; radiosensitivity, combinable only with a kinase-activity result: Mitui 2009/PMID 18634022, Scott 2002/PMID 11805335) and explicitly warns against inferring PS3/BS3 strength from the mere presence of the calibration table without confirming the variant itself was tested in those papers.
None of these three papers are present in this case's source registry, prefetch, or paper_extracts, so no direct verification of whether c.4324T>C (p.Y1442H) was assayed was possible from the materials provided.
The Sun et al. 2025 high-throughput dataset (PMID 40580951) is a candidate secondary PS3/BS3 source per the VCEP materials guidance, but no row for this exact variant was present in the excerpted Table S1 data in this bundle, and per guidance any such result would still need needs_human_review flagging given its uncertain 'approved assay' status under VCEP v1.5.
A ClinVar submitter (Genetic Services Laboratory, University of Chicago) explicitly documented the lack of functional studies for this variant, corroborating the absence of functional evidence.
Both PS3 and BS3 are therefore returned as not_assessed with needs_human_review flagged, rather than assuming either direction of functional effect.
REVEL (0.733) and SpliceAI (max delta 0.01) are the ATM VCEP v1.5's specified computational tools for PP3/BP4. Neither meets its respective PP3 pathogenic threshold, so PP3 is not met; REVEL falls in the missense-restricted BP4 gray zone under the applicable curator override, so BP4 is also not met despite a clean SpliceAI score.
The curator override (documented in vcep_materials.json gene_notes) blocks the splicing SpliceAI sub-path from being used for BP4 on missense variants, which changes the outcome from what the VCEP's literal text alone would produce (a clean SpliceAI <=0.1 would otherwise satisfy BP4).
BayesDel score (0.335891) was retrieved but is not used for PP3/BP4: no verified published calibration threshold is available to this pipeline for BayesDel.
Align-GVGD (grade C65) and SIFT/PolyPhen (damaging) predictions for Y1442H, reported in PMID:19781682 and PMID:24172824, are noted as corroborating in-silico context but are not part of the ATM VCEP v1.5's specified PP3/BP4 computational tools and do not independently trigger either criterion.
BP7 is not applicable because the variant is missense, not synonymous or deep intronic.
No criteria match.
Not met · 7 · evaluated, threshold not reached
PM2Not met: gnomAD v4.1 overall frequency 0.03911% (631/1,613,474 alleles) exceeds the 0.001% PM2 threshold.
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Reasoning
The ATM VCEP v1.5 PM2 rule allows PM2 Supporting when frequency is <=0.001% in gnomAD v4, with n=1 in a single subpopulation also sufficient. This variant has gnomAD v4.1 overall AF 0.03911% (631/1,613,474 alleles), grpmax FAF 0.047375%, and 0 homozygotes; its frequency exceeds 0.001%, so PM2 is not met.
Rule
ATM VCEP v1.5: PM2 Supporting requires frequency <=0.001% in gnomAD v4; n=1 in a single subpopulation is sufficient.
Evidence considered
ClinGen HBOP ATM VCEP v1.5 specifies PM2 Supporting for frequency <=0.001% in gnomAD v4; n=1 in a single subpopulation is also sufficient when applicable.
gnomAD v4.1 reports 631 alternate alleles among 1,613,474 alleles (AF 0.000391082, 0.03911%), grpmax FAF 0.00047375 (0.047375%), and zero homozygotes; the observed frequency is above the PM2 threshold.
PP3Not met: REVEL 0.733 falls just below the 0.7333 PP3 missense threshold.
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Reasoning
NM_000051.4:c.4324T>C, p.(Y1442H) is a missense variant. Under ATM VCEP v1.5, PP3 has two independent sub-paths available to a missense variant: (1) missense REVEL >0.7333, and (2) splicing SpliceAI >=0.2 (applicable to missense variants per the VCEP's own text, since any variant can potentially disrupt splicing). REVEL score = 0.733 (local REVEL v1.3 lookup), which falls just below the VCEP's PP3 missense threshold of >0.7333 - the score is 0.0003 short of the cutoff, effectively borderline. SpliceAI max delta score = 0.01 (DS_AG 0.004, DS_AL 0.006, DS_DG 0.004, DS_DL 0.01), far below the 0.2 splicing threshold, so the splicing sub-path also does not support PP3. Neither computational sub-path meets the VCEP's calibrated threshold, so PP3 is not met. Two published, non-VCEP-calibrated in-silico predictors (Align-GVGD grade C65 and SIFT score 0.00-0.01 damaging, per PMID:19781682; SIFT and PolyPhen both damaging, per PMID:24172824) also flag this variant as likely deleterious at the protein level, but neither Align-GVGD nor SIFT/PolyPhen is a tool the ATM VCEP v1.5 PP3 rule specifies or calibrates a threshold for, so they are noted as corroborating context only and do not independently trigger PP3.
Local REVEL v1.3 lookup: score = 0.733 for NM_000051.4:c.4324T>C - below the >0.7333 PP3 threshold by 0.0003.
SpliceAI Lookup: max delta score = 0.01 (DS_AG 0.004, DS_AL 0.006, DS_DG 0.004, DS_DL 0.01) - well below the >=0.2 PP3 splicing threshold.
PMID:19781682 (Tavtigian et al.): Y1442H listed among ATM missense substitutions graded C65 by Align-GVGD (the most deleterious Align-GVGD grade) and scored 0.00-0.01 by SIFT (damaging); this is corroborating non-VCEP-calibrated evidence only, since the ATM VCEP v1.5 PP3/BP4 rule does not specify Align-GVGD or SIFT thresholds.
PMID:24172824: reports p.Y1442H in two CLL patients; both SIFT and PolyPhen predicted the substitution to be damaging - again corroborating but non-VCEP-calibrated context, not used to trigger PP3.
Still missing
REVEL score (0.733) is only 0.0003 below the VCEP's PP3 threshold (>0.7333) - recommend human review given how close this is to a boundary that could flip the call with a marginal precision/rounding difference in the source lookup.
No VCEP-calibrated missense predictor beyond REVEL is available for this variant in the bundle (the Suppl_TableS1_PMID 40580951 AlphaMissense/CADD/boostDM columns were not matched to this specific variant's row in the retrieved materials).
PP5Not met: no ClinVar expert-panel pathogenic or likely pathogenic assertion exists for this variant.
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Reasoning
No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion exists. The record has zero expert-panel submissions; ordinary laboratory submissions and aggregate classifications were not used.
Rule
Apply only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.
Evidence considered
ClinVar variation 127385 for ATM c.4324T>C (p.Tyr1442His) reports an empty expert_panels object and the submission audit identifies zero expert-panel submissions.
BA1Not met: grpmax FAF 0.047375% is below the 0.5% BA1 threshold.
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Reasoning
The ATM VCEP v1.5 BA1 rule requires grpmax filtering AF >0.5% in gnomAD v4. The gnomAD v4.1 grpmax FAF is 0.00047375 (0.047375%), which is below 0.5%; therefore BA1 is not met.
Rule
ATM VCEP v1.5: BA1 Stand Alone requires grpmax Filtering AF >0.5% in gnomAD v4.
Evidence considered
ClinGen HBOP ATM VCEP v1.5 specifies BA1 when grpmax filtering AF is >0.5% in gnomAD v4.
gnomAD v4.1 reports overall AF 0.000391082 (0.03911%) and grpmax FAF 0.00047375 (0.047375%) for NM_000051.4:c.4324T>C; the maximum group value is below the BA1 threshold.
BS1Not met: grpmax FAF 0.047375% is just below the 0.05% BS1 threshold.
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Reasoning
The ATM VCEP v1.5 BS1 rule requires grpmax filtering AF >0.05% in gnomAD v4. The gnomAD v4.1 grpmax FAF is 0.00047375 (0.047375%), just below 0.05%; therefore BS1 is not met. The highest named subpopulation AF is 0.050769%, but the VCEP rule uses grpmax FAF, not the unfiltered highest subpopulation AF.
Rule
ATM VCEP v1.5: BS1 Strong requires grpmax Filtering AF >0.05% in gnomAD v4.
Evidence considered
ClinGen HBOP ATM VCEP v1.5 specifies BS1 Strong when grpmax filtering AF is >0.05% in gnomAD v4.
gnomAD v4.1 reports grpmax FAF 0.00047375 (0.047375%) and highest observed European non-Finnish subpopulation AF 0.000507693 (0.050769%); the applicable grpmax value does not exceed 0.05%.
BP4Not met: REVEL 0.733 falls in the 0.249-0.7333 gray zone, above the 0.249 BP4 benign cutoff.
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Reasoning
This variant is missense (p.(Y1442H)). Per the ATM VCEP v1.5 BP4 rule, the missense sub-path requires REVEL <=0.249, and the splicing sub-path requires SpliceAI <=0.1. Applying a lab curator override documented in this case's gene_notes (not part of the official ATM VCEP v1.5 text): for missense variants, BP4 must be evaluated using ONLY the missense REVEL sub-path, never the splicing SpliceAI sub-path, because a clean SpliceAI score only rules out a splicing mechanism and does not clear the variant's own missense/protein-level effect. REVEL = 0.733 falls in the override's defined 0.249-0.7333 gray zone (above the BP4 benign cutoff but below the PP3 pathogenic cutoff), so BP4 is not met. Note this explicitly changes the outcome versus the VCEP's literal text alone: SpliceAI max delta = 0.01 is well below the VCEP's stated BP4 splicing threshold of <=0.1, so under the VCEP text alone (which permits the splicing sub-path for any variant type, missense included, since 'any variant has the potential to impact splicing'), BP4 would be met via the splicing sub-path. The curator override blocks that route for missense variants and requires the missense-specific REVEL evidence, which does not clear the benign threshold, so the applied outcome here is BP4 not_met.
Rule
ATM VCEP v1.5 BP4: Missense REVEL <=0.249; Splicing SpliceAI <=0.1. Curator override restricts missense variants to the REVEL sub-path only (does not modify PP3).
Curator override (gene_notes in vcep_materials.json, not official VCEP text): for missense variants, evaluate BP4 using ONLY the REVEL missense sub-path; do not apply the SpliceAI splicing sub-path for missense variants even though the VCEP's own text would permit it. If REVEL falls in the 0.249-0.7333 gray zone or is unavailable, BP4 is not_met/not_assessed regardless of SpliceAI.
Local REVEL v1.3 lookup: score = 0.733, within the override's 0.249-0.7333 gray zone - above the BP4 benign threshold of <=0.249, so BP4 does not apply via the missense path.
SpliceAI Lookup: max delta score = 0.01, which would satisfy the VCEP's literal <=0.1 splicing threshold, but this sub-path is excluded for missense variants under the curator override, so it is not used to call BP4 met.
BP6Not met: no ClinVar expert-panel benign or likely benign assertion exists for this variant.
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Reasoning
No exact-variant ClinVar expert-panel Benign or Likely benign assertion exists. The record has zero expert-panel submissions; benign and likely benign ordinary laboratory submissions were not used.
Rule
Apply only for an exact-variant ClinVar expert-panel Benign or Likely benign classification.
Evidence considered
ClinVar variation 127385 for ATM c.4324T>C (p.Tyr1442His) reports an empty expert_panels object and the submission audit identifies zero expert-panel submissions.
PS1Not assessed: no established pathogenic variant producing the same p.Tyr1442His change was available for comparison.
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Reasoning
ATM VCEP v1.5 PS1 guide permits PS1 (Strong) for a missense variant that produces the same amino-acid change as an established pathogenic/likely pathogenic variant, provided splicing impact is ruled out for both alterations. The variant under assessment is NM_000051.4:c.4324T>C, p.(Tyr1442His). This bundle contains no identified comparator variant - i.e. no alternate nucleotide change (e.g. a different codon substitution) at codon 1442 that is independently classified as pathogenic/likely pathogenic in ClinVar or the literature and results in the same p.(Tyr1442His) substitution. The case's own ClinVar record for this exact variant (VariationID 127385) is itself classified Uncertain significance by all 23 usable submissions, so it cannot serve as the PS1 reference/comparator. OncoKB was also checked and returned no variant-specific reviewed classification (Unknown Oncogenic Effect, gene-level content only). No PS1 comparator search artifact specific to same-amino-acid-change variants was found in this bundle.
Rule
ATM VCEP v1.5 PS1: same amino acid change as an established P/LP variant, missense path, Strong (with splicing ruled out for both variants).
Evidence considered
ClinGen HBOP ATM VCEP v1.5 PS1 guide (ATM_PS1_1.5.pdf): standard missense PS1 path applies when the variant under assessment shares the same amino acid change as an established P/LP variant, with splicing ruled out for both.
ClinVar record for this exact variant (VariationID 127385) shows Uncertain significance across 23 usable submissions, so it cannot itself serve as an independent P/LP comparator for PS1.
OncoKB lookup for ATM Y1442H returned no variant-specific reviewed classification (classification: Unknown Oncogenic Effect, not_reviewed=true), offering no support for identifying a same-amino-acid-change comparator.
Still missing
No dedicated search was performed/returned for other nucleotide changes at codon 1442 producing the same p.(Tyr1442His) substitution that carry an independent pathogenic/likely pathogenic ClinVar or literature classification.
Splicing status of any hypothetical comparator variant (required prerequisite per VCEP PS1 guide) cannot be evaluated without first identifying a comparator.
PS3Not assessed: no VCEP-approved functional assay tested this variant, and a ClinVar submission notes functional studies are lacking.
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Reasoning
The ATM VCEP (HBOP v1.5) approves PS3/BS3 only from three specific kinase-activity assay papers (Mitui 2009/PMID 18634022, Barone 2009/PMID 19431188, Scott 2002/PMID 11805335), combinable with a radiosensitivity result from Mitui 2009 only, and explicitly requires confirming the variant under assessment was actually tested in one of these named papers rather than treating the table's presence as evidence per se. None of these three papers appear in this case's source registry or prefetched literature, so there is no evidence in the case bundle that NM_000051.4:c.4324T>C (p.Y1442H) was tested in any VCEP-approved functional assay. A ClinVar single-submitter record (SCV002068619, Genetic Services Laboratory, University of Chicago) explicitly states this variant lacks functional studies. The Sun et al. 2025 high-throughput ATM SNV functional dataset (PMID 40580951, Table S1) is listed as a candidate PS3/BS3 source in the VCEP materials package, but the bundle's excerpted Table S1 rows (matched on cHGVS) do not include a row for c.4324T>C/Y1442H, so no Combined_score/Classification/DeepATM_predicted value for this exact variant could be confirmed. No qualifying functional assay evidence is therefore available to apply PS3.
Rule
ATM VCEP v1.5 PS3: Use when a variant fails to rescue an ATM-specific feature only (e.g. phosphorylation of ATM-specific targets) = Supporting; fails both ATM-specific feature AND radiosensitivity = Moderate; Strong is explicitly disallowed ('Do not use as strong'). Requires the variant to have been tested in one of the three VCEP-approved assay papers.
Evidence considered
ClinVar submission SCV002068619 (Genetic Services Laboratory, University of Chicago) states directly: "due to the lack of functional studies, the clinical significance of the p.[Tyr1442His] variant..." - confirming no functional assay data was available to that laboratory for this variant.
None of the fetched full-text papers in paper_extracts.json (PMID 17393301, 25741868, 27153395, 21787400, 30303537, 24172824, 19781682) report a functional/kinase-activity/radiosensitivity assay result for c.4324T>C (p.Y1442H); PMID 24172824 reports only in-silico SIFT/PolyPhen predictions (both 'D'/damaging) for this variant in CLL patients, not a functional assay.
ATM VCEP v1.5 approved-assay table (clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx) requires the variant be confirmed as tested in one of PMID 18634022, 19431188, or 11805335 before PS3/BS3 strength can be assigned; none of these three papers are present in this case's source registry, so this prerequisite could not be verified.
Still missing
None of the three VCEP-approved kinase-activity/radiosensitivity assay papers (PMID 18634022, 19431188, 11805335) were retrieved for this case; need to check each directly to confirm whether p.Y1442H/c.4324T>C was among the tested variants.
The Sun et al. 2025 (PMID 40580951) Table S1 row for c.4324T>C was not present in the excerpted/prefetched portion of the spreadsheet in this bundle; the full spreadsheet needs to be queried for this exact cHGVS to obtain Combined_score, Classification, Confidence, and DeepATM_predicted before this source could be used, and even then a needs_human_review flag would be required since this paper post-dates the VCEP's own approved-assay table and its qualification as an approved assay is unresolved.
PS4Not assessed: reported in two contralateral breast-cancer and two CLL cases, but no case-control effect estimate met the p<=0.05, OR>=2 threshold.
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Reasoning
ATM HBOP VCEP v1.5 requires a case-control study with p<=0.05 and OR, HR, or RR >=2, or lower 95% CI >=1.5. The exact variant was observed in two contralateral breast-cancer cases and no unilateral breast-cancer cases in one study, but no variant-specific effect estimate, confidence interval, or p-value was reported. A second study observed p.Y1442H in two CLL samples without a control comparison. Neither source establishes the VCEP PS4 threshold.
Rule
ATM HBOP VCEP v1.5: Case-control studies; p-value <=0.05 AND (odds ratio, hazard ratio, or relative risk >=2 OR lower 95% CI >=1.5).
Evidence considered
ATM HBOP VCEP v1.5 PS4 rule: case-control study with p<=0.05 and OR, HR, or RR >=2, or lower 95% CI >=1.5.
PMID:17393301 Table 1 reports c.4324T>C (Y1442H) in 2 contralateral breast-cancer cases and none in the unilateral breast-cancer group, but supplies no variant-specific p-value, odds ratio, or confidence interval.
PMID:24172824 Table 1 reports p.Y1442H in two CLL samples; its 124-sample targeted-sequencing cohort has no matched control comparison for this variant.
Still missing
A variant-specific case-control analysis reporting p-value and OR, HR, or RR with confidence interval under the ATM HBOP VCEP threshold is needed.
PM3Not assessed: the reported breast-cancer and CLL cases are not A-T probands and provide no in-trans pathogenic allele evidence.
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Reasoning
The ATM ClinGen HBOP VCEP v1.5 PM3 framework applies a points-based approach for Ataxia-Telangiectasia, requiring affected probands with a confident or consistent A-T phenotype and information about a second pathogenic/likely pathogenic allele, phase, or homozygosity. The available exact-variant reports describe breast-cancer or CLL patients, not A-T probands, and do not establish the tested variant in trans with a VCEP-classified pathogenic/likely pathogenic ATM variant, homozygosity, or an eligible A-T phenotype. Therefore no PM3 points can be assigned from the available evidence.
Rule
ATM VCEP v1.5 PM3 points-based rule: evaluate unrelated A-T probands by phenotype confidence and allele phase/zygosity; PM3 Supporting=1 point, Moderate=2 points, Strong=4 points, Very Strong=8 points.
Evidence considered
The ATM HBOP VCEP v1.5 PM3/BP2 table assigns PM3 points per unrelated A-T proband: confident phenotype with confirmed in-trans phase = 4 points, phase unknown = 2 points, second variant unidentified/VUS = 1 point, and homozygous = 2 points per individual (maximum two individuals); consistent phenotypes receive half these values. Strength conversion is Supporting=1, Moderate=2, Strong=4, Very Strong=8 points.
PMID:17393301 reports c.4324T>C (p.Y1442H) in two breast-cancer patients in a contralateral-breast-cancer cohort, with no variant-specific segregation or phase information; this is not an A-T proband series.
PMID:24172824 reports p.Y1442H in two CLL patients, with no second ATM allele, phase information, A-T phenotype, or variant-specific segregation analysis reported.
No available evidence establishes a VCEP-classified pathogenic/likely pathogenic ATM allele in trans or qualifying homozygosity for this variant.
Still missing
A-T-affected proband observations for NM_000051.4:c.4324T>C (p.Tyr1442His) with phenotype confidence documented.
A second ATM variant in the same affected proband classified as pathogenic/likely pathogenic under the ATM VCEP framework.
Parental or other validated phasing demonstrating the variants are in trans, or qualifying evidence of homozygosity.
PP1Not assessed: the breast-cancer and CLL reports contain no variant-specific family segregation evidence.
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Reasoning
The ATM VCEP v1.5 provides an applicable PP1 rule for an autosomal-recessive condition: Supporting for segregation in 1 affected relative, Moderate for 2 affected relatives, and Strong for at least 3 affected relatives. The exact variant was reported in two breast-cancer patients in PMID:17393301 and in two CLL patients in PMID:24172824, but these reports do not provide variant-specific family segregation, affected-relative counts, phase/meioses, or phenotype-consistent pedigree evidence. Therefore PP1 cannot be assigned.
Rule
ATM VCEP v1.5 PP1: AR condition; Supporting for segregation in 1 affected relative, Moderate for 2 affected relatives, Strong for at least 3 affected relatives.
Evidence considered
ATM VCEP v1.5 PP1 rule: autosomal-recessive segregation in 1 affected relative supports PP1 Supporting, 2 affected relatives supports PP1 Moderate, and at least 3 affected relatives supports PP1 Strong.
PMID:17393301 lists c.4324T>C (p.Y1442H) in two contralateral breast-cancer patients but reports no variant-specific segregation analysis or additional clinical characterization.
PMID:24172824 lists p.Y1442H in two CLL patients but reports no family segregation or parental testing.
Still missing
Variant-specific family pedigrees and segregation results are not documented.
The number of affected relatives carrying the variant, informative meioses, and phenotype consistency are unavailable.
No validated segregation evidence is available to apply the ATM VCEP PP1 strength thresholds.
BS3Not assessed: no VCEP-approved functional assay or rescue data for this variant was available.
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Reasoning
Same evidence gap as PS3: the ATM VCEP restricts BS3 to the same three approved kinase-activity assay papers (PMID 18634022, 19431188, 11805335), which are not present in this case's retrieved literature, and no functional rescue data for c.4324T>C (p.Y1442H) was found in any fetched source. The ClinVar submission for this variant explicitly cites a lack of functional studies. No qualifying evidence supports application of BS3.
Rule
ATM VCEP v1.5 BS3: Use when a variant rescues both an ATM-specific feature AND radiosensitivity = Moderate; rescues either alone = Supporting. Requires the variant to have been tested in one of the three VCEP-approved assay papers.
Evidence considered
ClinVar submission SCV002068619 (Genetic Services Laboratory, University of Chicago) states directly: "due to the lack of functional studies, the clinical significance of the p.[Tyr1442His] variant..." - confirming no functional rescue/normal-readout data was available to that laboratory for this variant.
None of the fetched full-text papers in paper_extracts.json report a functional assay rescue result for c.4324T>C (p.Y1442H).
ATM VCEP v1.5 approved-assay table requires confirmation the variant was tested in one of the three named papers before BS3 strength can be assigned; this prerequisite could not be verified from the case's retrieved sources.
Still missing
Same as PS3: the three VCEP-approved assay papers were not retrieved for this case and need direct review to confirm whether this variant was tested (positively or negatively).
Sun et al. 2025 (PMID 40580951) Table S1 row for this exact variant was not present in the excerpted data; would need direct lookup, and even a functional/normal result there may not qualify as an 'approved assay' per VCEP caveats.
BP2Not assessed: no unaffected carrier with a pathogenic ATM variant in trans was documented.
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Reasoning
The ATM ClinGen HBOP VCEP v1.5 BP2 framework requires the variant in an unaffected non-A-T individual together with a pathogenic/likely pathogenic ATM variant in trans, with strength based on the number and certainty of such observations. The available exact-variant reports do not document unaffected non-A-T carriers, a pathogenic/likely pathogenic ATM variant in the same individual, or confirmed/unknown trans phase. Consequently no BP2 points can be assigned.
Rule
ATM VCEP v1.5 BP2 points-based rule: unaffected non-A-T carriers with a pathogenic/likely pathogenic ATM variant in trans receive -4 points if confirmed in trans, -2 if phase is unknown, and -2 in a laboratory setting or -1 in a database setting for homozygous observations; BP2 Supporting=-1, Moderate=-2, Strong<=-4 points.
Evidence considered
The ATM HBOP VCEP v1.5 PM3/BP2 table assigns BP2 points for an unaffected non-A-T individual carrying the variant with a pathogenic/likely pathogenic variant in trans: -4 points when confirmed in trans, -2 points when phase is unknown, and -2 points in a laboratory setting or -1 point in a database setting for homozygous observations (maximum -2 points for homozygous observations).
PMID:17393301 identifies p.Y1442H in breast-cancer patients but does not describe unaffected carriers, a second pathogenic/likely pathogenic ATM variant, or phase.
PMID:24172824 identifies p.Y1442H in CLL patients but does not describe unaffected carriers, a second pathogenic/likely pathogenic ATM variant, or phase.
The available evidence contains no eligible unaffected non-A-T co-occurrence observation for BP2.
Not applicable · 14· recorded as not applicableShow reasons ▾Hide reasons ▴PVS1N/ANot applicable: this is a missense substitution (p.Tyr1442His), and PVS1 applies only to null variants such as nonsense, frameshift, or splice-site changes.
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Reasoning
NM_000051.4:c.4324T>C is a missense substitution predicting NP_000042.3:p.(Tyr1442His) - a single amino acid substitution with no change to reading frame, no premature termination codon, no canonical splice-site disruption, no initiation-codon loss, and no exon/multi-exon deletion. The ATM VCEP v1.5 PVS1 decision guide (ATM_PVS1_1.5.pdf) is scoped explicitly to null variant classes: nonsense, frameshift, canonical +/-1,2 splice sites, initiation codon, and single/multi-exon deletion. This variant does not fall into any of those buckets, so the VCEP PVS1 decision tree is not entered and PVS1 does not apply. The pipeline's own generic PVS1 variant-assessment scaffold concurs, classifying consequence_class as 'missense' and explicitly declining to apply the generic PVS1 framework.
Rule
ATM VCEP v1.5 PVS1 - decision tree applies only to null-variant classes (nonsense, frameshift, canonical splice, initiation codon, exon deletion); missense variants are out of scope.
Evidence considered
case_summary.json normalization gives protein_3l NP_000042.3:p.(Tyr1442His), a missense change, not a null-variant class.
pvs1_variant_assessment.json: consequence_class='missense', canonical_splice_consensus=false, apply_generic_pvs1_framework=false, rationale states variant does not fall into generic PVS1 null-variant buckets of nonsense, frameshift, or canonical +/-1,2 splice consensus.
ATM VCEP v1.5 index guidance (ATM_PVS1_1.5.pdf) scopes the PVS1 decision tree to null variants only: nonsense, frameshift, canonical +/-1,2 splice sites, initiation codon, single/multi-exon deletion - missense substitutions are outside this decision tree's scope.
PS2VCEPNot applicable: the ATM VCEP designates PS2 as not applicable, and no confirmed de novo occurrence is documented.
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Reasoning
The ClinGen HBOP ATM VCEP version 1.5 framework explicitly designates PS2 as not applicable. No de novo occurrence with confirmed parental testing is documented for NM_000051.4:c.4324T>C (p.Tyr1442His).
VCEP rule
ATM VCEP v1.5: PS2 not applicable.
Evidence considered
The ATM VCEP v1.5 criterion table lists PS2 as Not Applicable.
The exact variant was reported in published case tables, but the extracted reports provide no parental testing or confirmed de novo status.
PM1VCEPNot applicable: the ATM VCEP defines no hotspot or critical-domain mutational-density rule for this gene.
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Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 specification explicitly marks PM1 as 'Not Applicable' for this gene (no hotspot/critical-functional-domain mutational density rule is defined). The VCEP-specific criteria combination takes precedence over generic ACMG/AMP domain-based PM1 reasoning. Consistent with this, a cancerhotspots.org search for ATM Y1442 returned no significant hotspot result.
VCEP rule
ATM VCEP v1.5: PM1 applicability = Not Applicable.
cancerhotspots.org search for ATM Y1442 returned search_status='no_result' / found=false, consistent with no statistically significant mutational hotspot at this residue, though this is supplementary context only since the VCEP already rules PM1 not applicable.
PM4N/ANot applicable: PM4 is restricted to stop-loss variants, and this is an internal missense substitution.
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Reasoning
The ATM VCEP v1.5 CSPEC restricts PM4 to stop-loss variants only ('Use for stop-loss variants', PM4 default strength Moderate). NM_000051.4:c.4324T>C is a missense substitution (p.Tyr1442His) at an internal codon, not a stop-loss variant, and involves no change in protein length (no in-frame insertion/deletion, no stop-codon loss, no repeat-region expansion/contraction). PM4's generic ACMG basis (protein length change from in-frame indels or stop-loss) is not met by a single-residue substitution, and the gene-specific VCEP rule for PM4 does not extend to ordinary missense changes.
Rule
ATM VCEP v1.5 PM4 - applicable only to stop-loss variants; this variant is a missense substitution, not stop-loss.
Evidence considered
case_summary.json cspec.criteria PM4 entry: defaultStrength Pathogenic Moderate, single rule 'Use for stop-loss variants.' - no broader missense or protein-length provision.
Variant is NP_000042.3:p.(Tyr1442His), a substitution missense change with no protein length alteration and no stop-codon involvement, so the sole ATM VCEP PM4 pathway (stop-loss) is not triggered.
PM5N/ANot applicable: the VCEP's PM5 rule covers only truncating variants, and this missense variant is not eligible.
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Reasoning
The ClinGen HBOP ATM VCEP v1.5 specification defines PM5 only as a truncation-cutoff rule (Supporting strength for frameshifting/truncating variants, or NMD-prone splice variants with PVS1_VS(RNA) applied, upstream of p.Arg3047) - it does not include a classic same-residue-different-missense-change PM5 sub-path. NM_000051.4:c.4324T>C is a missense substitution (p.(Tyr1442His)), not a truncating or splice variant, so the VCEP's PM5 rule does not apply to it. This is corroborated by the case's own pm5_candidates artifact, which independently flags this variant as ineligible for classic same-residue PM5 search under this gene's framework (pm5_mode='truncation_cutoff_gene_specific', eligible_for_classic_pm5_search=false).
Rule
ATM VCEP v1.5: PM5 = truncating/NMD-prone splice variants upstream of p.Arg3047 only; no missense same-residue sub-path defined, so not applicable to this missense variant.
Evidence considered
ClinGen HBOP ATM VCEP v1.5 PM5 rule text restricts PM5(Supporting) to frameshifting/truncating variants and NMD-prone splice variants with PVS1_VS(RNA) upstream of p.Arg3047 - it defines no missense same-residue comparator sub-path.
pm5_candidates.json for this case confirms pm5_mode='truncation_cutoff_gene_specific' and eligible_for_classic_pm5_search=false, with recommendation.level='not_applicable' because PM5 in this VCEP is a truncation-cutoff rule rather than classic same-residue missense PM5.
PM6VCEPNot applicable: the ATM VCEP designates PM6 as not applicable, and no assumed de novo event is documented.
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Reasoning
The ClinGen HBOP ATM VCEP version 1.5 framework explicitly designates PM6 as not applicable. The available exact-variant reports do not document an assumed de novo event without parental testing.
VCEP rule
ATM VCEP v1.5: PM6 not applicable.
Evidence considered
The ATM VCEP v1.5 criterion table lists PM6 as Not Applicable.
The exact variant reports contain no evidence of an assumed de novo occurrence.
PP2VCEPNot applicable: the ATM VCEP designates PP2 as not applicable for this gene.
Details ▾Hide ▴
Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 specification explicitly marks PP2 as 'Not Applicable' for this gene, superseding the generic ACMG/AMP missense-gene-mechanism PP2 rule.
VCEP rule
ATM VCEP v1.5: PP2 applicability = Not Applicable.
BS4VCEPNot applicable: the ATM VCEP designates BS4 as not applicable, and no variant-specific non-segregation evidence is documented.
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Reasoning
The ClinGen HBOP ATM VCEP version 1.5 framework explicitly designates BS4 as not applicable. No reliable variant-specific non-segregation evidence is documented in the reviewed reports.
VCEP rule
ATM VCEP v1.5: BS4 not applicable.
Evidence considered
The ATM VCEP v1.5 criterion table lists BS4 as Not Applicable.
The reviewed exact-variant reports do not describe unaffected carriers, non-segregation in informative families, or other variant-specific BS4 evidence.
BP1VCEPNot applicable: the ATM VCEP designates BP1 as not applicable for this gene.
Details ▾Hide ▴
Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 specification explicitly marks BP1 as 'Not Applicable' for this gene, superseding the generic ACMG/AMP 'missense variant in a gene where only truncating variants cause disease' BP1 rule.
VCEP rule
ATM VCEP v1.5: BP1 applicability = Not Applicable.
BP3VCEPNot applicable: the ATM VCEP designates BP3 as not applicable; this is a missense change, not an in-frame repeat-region indel.
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Reasoning
The ATM VCEP v1.5 CSPEC explicitly marks BP3 as 'Not Applicable' for this gene, superseding the generic ACMG in-frame indel/repeat-region provision. No VCEP-specific alternative rule is provided. The variant is also a missense substitution, not an in-frame insertion/deletion in a repeat region, so BP3's underlying rationale (protein-length-neutral change in a non-conserved repeat region) is not structurally relevant regardless.
VCEP rule
ATM VCEP v1.5 BP3 marked Not Applicable for this gene.
Evidence considered
case_summary.json cspec.criteria: BP3 entry has 'applicability': 'Not Applicable' with no rules block - the ATM VCEP has explicitly disabled BP3 gene-wide.
BP7N/ANot applicable: BP7 covers only synonymous and deep intronic variants; this is a missense change.
Details ▾Hide ▴
Reasoning
NM_000051.4:c.4324T>C is a missense variant (p.(Y1442H), NP_000042.3), not a synonymous/silent substitution and not a deep intronic variant. The ATM VCEP v1.5 BP7 rule applies only to synonymous and deep intronic variants (further than +7/-21 at donor/acceptor sites, respectively) or to variants with an observed lack of aberrant RNA splicing defect (BP7(RNA)). No RNA/splicing assay data for this variant is present in the case bundle, and the variant class itself (missense) falls outside BP7's scope regardless. BP7 is not applicable to this variant.
Rule
ATM VCEP v1.5 BP7: Synonymous/deep intronic variants only (or BP7(RNA) for observed lack of aberrant RNA defect in silent/intronic variants). Not applicable to missense variants.
Evidence considered
ATM VCEP v1.5 BP7 rule (cspec): applies to synonymous and deep intronic variants (or observed lack of RNA splicing defect for silent/intronic variants) - variant class here is missense p.(Y1442H), outside BP7's defined scope.
AF 0.00039 · 631 / 1,613,474 alleles · 0 hom · FAF 0.00047
European (non-Finnish)599 / 1,179,848
0.00051
European (Finnish)14 / 64,018
0.00022
Remaining individuals11 / 62,432
0.00018
African/African American7 / 74,930
9.3e-05
0 alternate alleles recorded in 6 other groups: Admixed American, Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish.
gnomAD v2.1
AF 0.0003 · 86 / 282,268 alleles · 0 hom · FAF 0.00053
European (non-Finnish)78 / 128,820
0.00061
Remaining individuals2 / 7,192
0.00028
European (Finnish)6 / 25,106
0.00024
0 alternate alleles recorded in 5 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000391082; MAF= 0.03911%, 631/1613474 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000507693; MAF= 0.05077%, 599/1179848 alleles, homozygotes = 0); grpmax FAF= 0.00047375.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000304675; MAF= 0.03047%, 86/282268 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000605496; MAF= 0.06055%, 78/128820 alleles, homozygotes = 0); grpmax FAF= 0.00053252.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0002171788467803236, 4/18418 alleles, homozygotes = 0).
PP3Not met: REVEL 0.733 falls just below the 0.7333 PP3 missense threshold.
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Reasoning
NM_000051.4:c.4324T>C, p.(Y1442H) is a missense variant. Under ATM VCEP v1.5, PP3 has two independent sub-paths available to a missense variant: (1) missense REVEL >0.7333, and (2) splicing SpliceAI >=0.2 (applicable to missense variants per the VCEP's own text, since any variant can potentially disrupt splicing). REVEL score = 0.733 (local REVEL v1.3 lookup), which falls just below the VCEP's PP3 missense threshold of >0.7333 - the score is 0.0003 short of the cutoff, effectively borderline. SpliceAI max delta score = 0.01 (DS_AG 0.004, DS_AL 0.006, DS_DG 0.004, DS_DL 0.01), far below the 0.2 splicing threshold, so the splicing sub-path also does not support PP3. Neither computational sub-path meets the VCEP's calibrated threshold, so PP3 is not met. Two published, non-VCEP-calibrated in-silico predictors (Align-GVGD grade C65 and SIFT score 0.00-0.01 damaging, per PMID:19781682; SIFT and PolyPhen both damaging, per PMID:24172824) also flag this variant as likely deleterious at the protein level, but neither Align-GVGD nor SIFT/PolyPhen is a tool the ATM VCEP v1.5 PP3 rule specifies or calibrates a threshold for, so they are noted as corroborating context only and do not independently trigger PP3.
Local REVEL v1.3 lookup: score = 0.733 for NM_000051.4:c.4324T>C - below the >0.7333 PP3 threshold by 0.0003.
SpliceAI Lookup: max delta score = 0.01 (DS_AG 0.004, DS_AL 0.006, DS_DG 0.004, DS_DL 0.01) - well below the >=0.2 PP3 splicing threshold.
PMID:19781682 (Tavtigian et al.): Y1442H listed among ATM missense substitutions graded C65 by Align-GVGD (the most deleterious Align-GVGD grade) and scored 0.00-0.01 by SIFT (damaging); this is corroborating non-VCEP-calibrated evidence only, since the ATM VCEP v1.5 PP3/BP4 rule does not specify Align-GVGD or SIFT thresholds.
PMID:24172824: reports p.Y1442H in two CLL patients; both SIFT and PolyPhen predicted the substitution to be damaging - again corroborating but non-VCEP-calibrated context, not used to trigger PP3.
Still missing
REVEL score (0.733) is only 0.0003 below the VCEP's PP3 threshold (>0.7333) - recommend human review given how close this is to a boundary that could flip the call with a marginal precision/rounding difference in the source lookup.
No VCEP-calibrated missense predictor beyond REVEL is available for this variant in the bundle (the Suppl_TableS1_PMID 40580951 AlphaMissense/CADD/boostDM columns were not matched to this specific variant's row in the retrieved materials).
BP4Not met: REVEL 0.733 falls in the 0.249-0.7333 gray zone, above the 0.249 BP4 benign cutoff.
Details ▾Hide ▴
Reasoning
This variant is missense (p.(Y1442H)). Per the ATM VCEP v1.5 BP4 rule, the missense sub-path requires REVEL <=0.249, and the splicing sub-path requires SpliceAI <=0.1. Applying a lab curator override documented in this case's gene_notes (not part of the official ATM VCEP v1.5 text): for missense variants, BP4 must be evaluated using ONLY the missense REVEL sub-path, never the splicing SpliceAI sub-path, because a clean SpliceAI score only rules out a splicing mechanism and does not clear the variant's own missense/protein-level effect. REVEL = 0.733 falls in the override's defined 0.249-0.7333 gray zone (above the BP4 benign cutoff but below the PP3 pathogenic cutoff), so BP4 is not met. Note this explicitly changes the outcome versus the VCEP's literal text alone: SpliceAI max delta = 0.01 is well below the VCEP's stated BP4 splicing threshold of <=0.1, so under the VCEP text alone (which permits the splicing sub-path for any variant type, missense included, since 'any variant has the potential to impact splicing'), BP4 would be met via the splicing sub-path. The curator override blocks that route for missense variants and requires the missense-specific REVEL evidence, which does not clear the benign threshold, so the applied outcome here is BP4 not_met.
Rule
ATM VCEP v1.5 BP4: Missense REVEL <=0.249; Splicing SpliceAI <=0.1. Curator override restricts missense variants to the REVEL sub-path only (does not modify PP3).
Curator override (gene_notes in vcep_materials.json, not official VCEP text): for missense variants, evaluate BP4 using ONLY the REVEL missense sub-path; do not apply the SpliceAI splicing sub-path for missense variants even though the VCEP's own text would permit it. If REVEL falls in the 0.249-0.7333 gray zone or is unavailable, BP4 is not_met/not_assessed regardless of SpliceAI.
Local REVEL v1.3 lookup: score = 0.733, within the override's 0.249-0.7333 gray zone - above the BP4 benign threshold of <=0.249, so BP4 does not apply via the missense path.
SpliceAI Lookup: max delta score = 0.01, which would satisfy the VCEP's literal <=0.1 splicing threshold, but this sub-path is excluded for missense variants under the curator override, so it is not used to call BP4 met.
BP7N/ANot applicable: BP7 covers only synonymous and deep intronic variants; this is a missense change.
Details ▾Hide ▴
Reasoning
NM_000051.4:c.4324T>C is a missense variant (p.(Y1442H), NP_000042.3), not a synonymous/silent substitution and not a deep intronic variant. The ATM VCEP v1.5 BP7 rule applies only to synonymous and deep intronic variants (further than +7/-21 at donor/acceptor sites, respectively) or to variants with an observed lack of aberrant RNA splicing defect (BP7(RNA)). No RNA/splicing assay data for this variant is present in the case bundle, and the variant class itself (missense) falls outside BP7's scope regardless. BP7 is not applicable to this variant.
Rule
ATM VCEP v1.5 BP7: Synonymous/deep intronic variants only (or BP7(RNA) for observed lack of aberrant RNA defect in silent/intronic variants). Not applicable to missense variants.
Evidence considered
ATM VCEP v1.5 BP7 rule (cspec): applies to synonymous and deep intronic variants (or observed lack of RNA splicing defect for silent/intronic variants) - variant class here is missense p.(Y1442H), outside BP7's defined scope.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.733. BayesDel score = 0.335891.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Recorded publications
Rare, evolutionarily unlikely missense substitutions in ATM confer increased risk of breast cancer.
Tavtigian SV et al. · 2009
The paper explicitly names p.Y1442H among rare ATM missense substitutions graded C65 by Align-GVGD and/or scored 0.00 by SIFT. It presents the variant in an in-silico analysis and reports no variant-specific segregation result, family data, or non-segregation evidence for p.Y1442H.
Figure 2. ATM Missense Substitutions Graded C65 by Align-GVGD and/or Scored 0.00 by SIFT
Y1442H
Figure 2A, page 439; Results, Analysis of Rare Missense Substitutions
Rare variants in the ATM gene and risk of breast cancer.
Goldgar DE et al. · 2011
The paper investigates other rare ATM variants in relation to breast-cancer risk and includes family-based analyses, but it does not report ATM c.4324T>C or p.Y1442H and provides no variant-specific segregation or non-segregation evidence for this variant.
The ataxia-telangiectasia mutated (ATM) gene (MIM ID 208900) encodes a protein kinase that plays a major role in activating cellular responses to DNA double-strand breaks through downstream phosphorylation of central players in the DNA damage-response pathways, including BRCA1, p53, and Chk2 [1].
Introduction, paragraph 1; Results and Discussion sections on rare ATM variants and breast-cancer risk
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
Richards S et al. · 2015
This paper does not report the ATM variant c.4324T>C or NP_000042.3:p.(Y1442H); it presents general ACMG/AMP variant interpretation standards, not variant-specific functional data.
The variant classification approach described in this article is meant to be applicable to variants in all Mendelian genes, whether identified by single gene tests, multigene panels, exome sequencing, or genome sequencing.
Introduction, General considerations; page 2
Evaluation of ACMG-Guideline-Based Variant Classification of Cancer Susceptibility and Non-Cancer-Associated Genes in Families Affected by Breast Cancer.
Gene-level cohort statistics only (4.9% of families had LP/P ATM+CHEK2 mutations); does not mention c.4324T>C or p.(Y1442H) or provide functional data.
As shown in Figure 3A, in these 389 individuals representing 243 families without identified BRCA1/2 mutations, 2.5% were found to have LP or P mutations in high-risk breast cancer susceptibility genes TP53, CDH1, and PALB2, and 4.9% were found to have such mutations in ATM and CHEK2.
Results, paragraph discussing Figure 3A
Familial breast cancer and DNA repair genes: Insights into known and novel susceptibility genes from the GENESIS study, and implications for multigene panel testing.
Does not mention c.4324T>C or p.(Y1442H); reports gene-level ATM LoF vs missense breast cancer risk association only, no functional assay data for this variant.
Both LoF and MV in PALB2, ATM and CHEK2 were associated with an increased BC risk, but carriers of an ATM LoF had a significantly higher risk of developing BC than carriers of an ATM MV (ORLoF = 17.4 vs. ORMV = 1.6; pHet = 0.002) (Table 2).
Results, Breast cancer risk assessment, paragraph immediately preceding Table 2
The spectrum of ATM missense variants and their contribution to contralateral breast cancer.
Broeks A et al. · 2008
The ATM missense variant c.4324T>C, resulting in p.(Y1442H), was identified in two patients in the contralateral breast cancer group and was not reported in the unilateral breast cancer group in Table 1. The paper lists the variant as novel at the time of the study. No variant-specific functional assay, segregation analysis, or additional clinical characterization was reported for this variant.
Table 1, ATM missense variant and truncating mutation spectrum
Feasibility of targeted next-generation sequencing of the TP53 and ATM genes in chronic lymphocytic leukemia.
Mansouri L et al. · 2014
The paper reports ATM p.Y1442H in two chronic lymphocytic leukemia patients, corresponding to the c.4324T>C substitution. The variants were listed in the ATM mutation table with read depth and allele frequency, and SIFT and PolyPhen predicted a damaging effect. The paper does not report parental testing, family segregation, or a variant-specific functional assay.
S10 ATM chr11:108160416 29 T4Cc Non-synonymous p.Y1442H 671 0.17 D D Trisomy 12 M
S74 ATM chr11:108160416 29 T4Cc Non-synonymous p.Y1442H 85 0.26 D D None U
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= 0.000391082; MAF= 0.03911%, 631/1613474 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000507693; MAF= 0.05077%, 599/1179848 alleles, homozygotes = 0); grpmax FAF= 0.00047375.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000304675; MAF= 0.03047%, 86/282268 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000605496; MAF= 0.06055%, 78/128820 alleles, homozygotes = 0); grpmax FAF= 0.00053252.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.0002171788467803236, 4/18418 alleles, homozygotes = 0).
ClinVar
This variant has been reported in ClinVar as Uncertain significance (16 clinical laboratories) and as Likely benign (5 clinical laboratories) and as Benign (2 clinical laboratories) and as likely benign (1 clinical laboratory) and as Likely Benign (1 clinical laboratory). (ClinVarID = 127385)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.733. BayesDel score = 0.335891.
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 previously been reported in somatic cancers (COSMIC; COSV99069707, n = 3 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
This variant was interpreted by pipeline 7.1.5.
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