ATM c.7243G>C, p.(Ala2415Pro)

Reasoning

PM2 is met at Supporting strength. The ATM VCEP v1.5 specifies PM2_Supporting for a frequency of <=0.001% in gnomAD v4, including a variant observed once in a single subpopulation. The exact variant is absent from gnomAD v4.1, which is compatible with and exceeds the required rarity threshold; it is also absent from gnomAD v2.1 and gnomAD-Canada v1.0.

Rule

Frequency <=0.001% in gnomAD v4 dataset; if n=1 in a single subpopulation, PM2_Supporting applies

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 specifies PM2_Supporting at frequency <=0.001% in the gnomAD v4 dataset and states that n=1 in a single subpopulation is sufficiently rare.
• The exact variant NM_000051.4:c.7243G>C (NC_000011.10:g.108329174G>C) is absent from gnomAD v4.1; no population allele count or frequency is reported, and the variant therefore does not exceed the PM2 frequency ceiling.
• The exact variant is also reported as absent from gnomAD v2.1 and gnomAD-Canada v1.0, providing concordant population rarity observations.

Sources

Reasoning

PVS1 is not met. NM_000051.4:c.7243G>C is a missense substitution, p.(Ala2415Pro), not a null variant. It is not at a canonical splice dinucleotide, and SpliceAI predicts no significant splice impact (maximum delta 0.012); thus there is no evidence that it produces a premature termination codon, NMD, exon loss, or loss of protein length. The ATM VCEP PVS1 decision guide applies to null variant classes and therefore does not apply to this missense consequence.

Rule

ATM VCEP v1.5 PVS1 decision guide: PVS1 is for null variants in ATM, a gene with established loss-of-function disease mechanism.

Evidence considered

• The normalized consequence is NM_000051.4:c.7243G>C, NP_000042.3:p.(Ala2415Pro), a single amino-acid substitution with unchanged protein length.
• The ATM VCEP v1.5 PVS1 guide specifies PVS1 for null variants (nonsense, frameshift, canonical ±1/2 splice variants, initiation-codon variants, or single/multi-exon deletions); the present variant is none of these classes.
• SpliceAI maximum delta is 0.012, below the reported threshold for a significant predicted splice effect; no splice-mediated truncation or NMD mechanism is supported.

Sources

Reasoning

PM4 is not met. Under the ATM VCEP v1.5 specification, PM4 is restricted to stop-loss variants. This variant is the missense substitution p.(Ala2415Pro), with no stop-loss event and no protein-length change.

Rule

ATM VCEP v1.5 PM4: use for stop-loss variants.

Evidence considered

• The ATM VCEP v1.5 PM4 rule is: ‘Use for stop-loss variants.’
• The normalized protein consequence is p.(Ala2415Pro), a missense substitution; the predicted protein begins and ends at the same positions as reference, supporting no length alteration.

Sources

Reasoning

The variant is a missense substitution, with REVEL 0.512 below the ATM VCEP PP3 threshold (>0.7333) and SpliceAI max delta 0.012 below the ATM VCEP splice threshold (≥0.2); PVS1/PVS1_Variable(RNA) is not applied.

Rule

Missense: REVEL >.7333; splicing: predicted impact via SpliceAI ≥0.2 for silent, missense/in-frame, and intronic variants outside donor and acceptor 1,2 sites.

Evidence considered

• LOOKUP variant_type: missense, NM_000051.4:c.7243G>C (NP_000042.3:p.(Ala2415Pro)).
• LOOKUP pvs1_or_pvs1_variable_rna_applied: FALSE — the variant is missense and the case assessment does not apply PVS1 or PVS1_Variable(RNA).
• LOOKUP revel_score: 0.512 for this missense variant.
• LOOKUP spliceai_score: maximum delta score 0.012 (DS_DL 0.012; the case summary rounds this to 0.01).
• LOOKUP computational_evidence_assessment: available computational evidence does not provide convergent calibrated support for a deleterious effect; REVEL is in the intermediate range and SpliceAI predicts no significant splice impact.
• CHECKLIST pp3_1: Has splice analysis been considered for this variant type, including missense, frameshift, nonsense, etc., as any variant has the potential to impact splicing which may preclude any expected protein effects? — TRUE — SpliceAI was assessed for this missense variant.
• CHECKLIST pp3_2: Is PVS1 or PVS1_Variable(RNA) applied? If so, PP3 for splice predictions may not be applied in addition. — FALSE — Neither PVS1 nor PVS1_Variable(RNA) is applied.
• CHECKLIST pp3_3: Do multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.)? — FALSE — REVEL 0.512 does not exceed the VCEP threshold and SpliceAI 0.012 does not support splice disruption.
• CHECKLIST pp3_4: Has caution been used in applying the wrong type of computational evidence (pro)? — TRUE — The missense REVEL path and splice-impact path were evaluated against their specified VCEP thresholds without treating an uncalibrated BayesDel score as evidence.
• CHECKLIST pp3_5: Have algorithms using the same or very similar input been avoided as independent evidence, since each algorithm should not be counted as an independent? — TRUE — Predictor outputs were not counted as independent additive evidence; only the specified REVEL and SpliceAI paths were assessed.
• CHECKLIST pp3_6: For a missense variant, is the REVEL score >.7333? — FALSE — REVEL is 0.512.
• CHECKLIST pp3_7: For a silent, missense/in-frame, or intronic variant outside of donor and acceptor 1,2 sites, is splicing impact predicted via SpliceAI ≥0.2? — FALSE — the variant is missense, but SpliceAI max delta is 0.012.
• Sun et al. Table S1 reports the exact variant as missense with REVEL 0.512 and a non-functional combined classification, but its predictor fields are corroborative and do not meet the ATM VCEP PP3 thresholds.

Sources

Reasoning

No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic assertion is present. The exact ClinVar record has one Ambry Genetics submission of Uncertain significance with single-submitter review status; it is not an expert-panel assertion and cannot support PP5.

Rule

PP5 may be applied only for an exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.

Evidence considered

• ClinVar variation 1757879 is an exact transcript-HGVS match for NM_000051.4:c.7243G>C and contains one Ambry Genetics Uncertain significance submission with 'criteria provided, single submitter' review status; the submission audit identifies zero expert-panel submissions.

Still missing

• An exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification.

Sources

Reasoning

BA1 is not met. The ATM VCEP v1.5 specifies BA1 when the gnomAD v4 group maximum filtering allele frequency is greater than 0.5%. This variant is absent from gnomAD v4.1, so the BA1 threshold is not reached.

Rule

Grpmax Filtering AF >0.5% in gnomAD v4 dataset

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 specifies BA1 as applicable at Grpmax Filtering AF >0.5% in the gnomAD v4 dataset.
• The exact variant NM_000051.4:c.7243G>C (NC_000011.10:g.108329174G>C) is reported as absent from gnomAD v4.1; therefore no group-maximum allele frequency exceeding 0.5% is available.

Sources

Reasoning

BS1 is not met. The ATM VCEP v1.5 specifies BS1 when the gnomAD v4 group maximum filtering allele frequency is greater than 0.05%. This variant is absent from gnomAD v4.1, so the BS1 threshold is not reached.

Rule

Grpmax Filtering AF >0.05% in gnomAD v4 dataset

Evidence considered

• ClinGen HBOP ATM VCEP v1.5 specifies BS1 as applicable at Grpmax Filtering AF >0.05% in the gnomAD v4 dataset.
• The exact variant NM_000051.4:c.7243G>C (NC_000011.10:g.108329174G>C) is reported as absent from gnomAD v4.1; therefore no allele frequency exceeding 0.05% is available.

Sources

Reasoning

The available direct functional result classifies NM_000051.4:c.7243G>C (p.Ala2415Pro) as Non-functional, which does not show rescue or absence of a damaging effect. No variant-specific evidence demonstrates rescue of an ATM-specific feature or radiosensitivity. BS3 is therefore not met.

Rule

ATM VCEP v1.5 BS3: use moderate when both an ATM-specific feature and radiosensitivity are rescued; use supporting when either is rescued.

Evidence considered

• The ATM VCEP v1.5 BS3 rule requires rescue of both an ATM-specific feature and radiosensitivity for moderate BS3, or rescue of either feature for supporting BS3.
• The exact variant row in Sun et al. Table S1 is directly measured (DeepATM_predicted=No) and classified Non-functional, not Functional; this is inconsistent with a benign rescue result.
• The ATM VCEP-approved assay table was consulted, but it provides assay calibration rather than a variant-specific rescue result and does not establish BS3 for this variant.
• CHECKLIST bs3_1: Is the evidence a well-established in vitro or in vivo functional study showing no damaging effect on protein function or splicing? — FALSE — The direct result for this variant is classified Non-functional, not as showing preserved function or normal splicing.
• CHECKLIST bs3_2: For protein evidence, have the detailed notes on ATM-specific assays been consulted? — TRUE — The ATM VCEP-specific kinase-activity and radiosensitivity assay guidance was reviewed.
• CHECKLIST bs3_3: For RNA evidence, has BP7_RNA been used and has strength been modulated based on assay quality and quantity (curator discretion)? — NA — This is a missense variant with direct prime-editing functional evidence, not an RNA assay.
• CHECKLIST bs3_4: Does the variant rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity? — NA — No variant-specific rescue measurements for both features were provided.
• CHECKLIST bs3_5: Does the variant rescue EITHER an ATM specifc feature OR rescue radiosensitivity? — NA — No variant-specific rescue measurement for either feature was provided.

Still missing

• No variant-specific rescue data for an ATM-specific feature or radiosensitivity were found.

Sources

Reasoning

For this missense variant, the governing ATM VCEP missense BP4 path requires REVEL ≤0.249; the observed REVEL is 0.512. Although SpliceAI is low (0.012), the case-specific BP4 override requires missense variants to use only the missense path and does not allow clean SpliceAI to establish BP4 for a missense protein effect.

Rule

Missense: REVEL ≤.249; splicing: no predicted impact via SpliceAI ≤0.1.

Evidence considered

• LOOKUP variant_type: missense, NM_000051.4:c.7243G>C (NP_000042.3:p.(Ala2415Pro)).
• LOOKUP bp7_variable_rna_applied: FALSE — no BP7_Variable(RNA) code is applied and the variant is not in a BP7-eligible class.
• LOOKUP revel_score: 0.512 for this missense variant.
• LOOKUP spliceai_score: maximum delta score 0.012.
• LOOKUP computational_evidence_assessment: SpliceAI suggests no splice impact, but REVEL is not in the benign BP4 range; the evidence is not convergent for a benign computational conclusion.
• CHECKLIST bp4_1: Has splice analysis been considered for this variant type, including missense, frameshift, nonsense, etc., as any variant has the potential to impact splicing which may preclude any expected protein effects? — TRUE — SpliceAI was assessed for this missense variant.
• CHECKLIST bp4_2: Is BP7_Variable(RNA) applied? If so, BP4 for splice predictions may not be applied in conjunction with it. — FALSE — BP7_Variable(RNA) is not applied.
• CHECKLIST bp4_3: Do multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)? — FALSE — only the splice predictor is clearly benign-direction; REVEL 0.512 is intermediate rather than benign-direction.
• CHECKLIST bp4_4: Has caution been used in applying the wrong type of compu? — TRUE — The missense REVEL path was used, and the low SpliceAI result was not used to clear the missense effect under the case-specific override.
• CHECKLIST bp4_5: Have algorithms using the same or very similar input been avoided as independent evidence, since each algorithm cannot be counted as an independent criterion? — TRUE — Predictor outputs were not counted as independent additive evidence.
• CHECKLIST bp4_6: For a missense variant, is the REVEL score ≤.249? — FALSE — REVEL is 0.512.
• CHECKLIST bp4_7: Is there no predicted impact via splicing, with SpliceAI ≤0.1? — TRUE — SpliceAI maximum delta is 0.012, which is ≤0.1; this does not establish BP4 for this missense variant because the case-specific override restricts missense BP4 to REVEL.
• The case-specific BP4 missense/splicing policy explicitly changes the outcome from a literal application of the VCEP's alternative splice wording: clean SpliceAI cannot establish BP4 for a missense variant when REVEL is in the 0.249–0.7333 gray zone.

Sources

Reasoning

No exact-variant ClinVar expert-panel Benign or Likely benign assertion is present. The exact ClinVar record has one non-expert Ambry Genetics Uncertain significance submission, which cannot support BP6.

Rule

BP6 may be applied only for an exact-variant ClinVar expert-panel Benign or Likely benign classification.

Evidence considered

• ClinVar variation 1757879 is an exact transcript-HGVS match for NM_000051.4:c.7243G>C and contains one Ambry Genetics Uncertain significance submission with 'criteria provided, single submitter' review status; the submission audit identifies zero expert-panel submissions.

Still missing

• An exact-variant ClinVar expert-panel Benign or Likely benign classification.

Sources

Reasoning

The variant is a missense change, p.Ala2415Pro, and the ATM VCEP permits PS1 for a missense change only when the same amino-acid change has been established as pathogenic and splicing has been ruled out for both alterations. The case bundle contains no established pathogenic same-amino-acid comparator and no comparator-specific splicing evidence; the current variant's SpliceAI result is low (maximum delta 0.012), but that alone cannot establish PS1.

Rule

Use for missense changes as long as splicing is ruled-out for both alterations; use the ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.

Evidence considered

• Variant normalization identifies NM_000051.4:c.7243G>C as the missense substitution NP_000042.3:p.(Ala2415Pro).
• The ATM VCEP PS1 guidance requires the same amino-acid change as an established pathogenic variant for the missense path and requires splicing to be ruled out for both alterations.
• SpliceAI reports no significant splice impact for the current variant, with maximum delta score 0.012.
• No established pathogenic same-amino-acid comparator or comparator-specific splice evidence is present in the consolidated case-evidence bundle.
• CHECKLIST ps1_1: Is the variant a missense change with the same amino acid change as a previously established pathogenic variant regardless of nucleotide change? — FALSE — The variant is missense, but no previously established pathogenic p.Ala2415Pro comparator is documented.
• CHECKLIST ps1_2: For a missense change, has a splice defect been ruled out for both alterations? — NA — Splicing is not predicted for the current variant, but no comparator alteration was identified for which splicing could also be assessed.
• CHECKLIST ps1_3: Is the variant a splicing variant? — FALSE — The variant is an exonic missense substitution in exon 49.
• CHECKLIST ps1_4: For a splicing variant, does the ATM PS1 Splicing table show similar predictions or observations of splice defect? — NA — The variant is not a splicing variant, so the ATM PS1 Splicing-table path is not applicable.

Still missing

• No previously established pathogenic ATM variant with the same p.Ala2415Pro amino-acid change was identified in the case evidence bundle.
• No comparator variant was identified, so splicing has not been established as ruled out for both alterations.

Sources

Reasoning

The variant is directly represented in the Sun et al. ATM prime-editing saturation screen as Non-functional with DeepATM_predicted=No and Medium-high confidence, which is supportive of a damaging functional effect. However, the ATM VCEP PS3/BS3 specification calibrates approved evidence using specific ATM kinase/radiosensitivity assays and states that the current variant must be confirmed in those papers; the Sun assay is not one of the VCEP-calibrated assays. Therefore PS3 is not assigned pending human review of whether this newer direct assay can be accepted under the current VCEP specification.

Rule

ATM VCEP v1.5 PS3: do not use as strong; use moderate when both an ATM-specific feature and radiosensitivity fail; use supporting when an ATM-specific feature alone fails; do not use radiosensitivity-only evidence.

Evidence considered

• The ATM VCEP v1.5 framework applies to this ATM variant and specifies PS3 as applicable, prohibits PS3 at strong strength, permits moderate only when both an ATM-specific feature and radiosensitivity fail, and permits supporting when an ATM-specific feature alone fails.
• The ATM VCEP-approved assay table identifies specific ATM kinase-activity assays and a limited radiosensitivity assay as the calibrated evidence base; it requires confirmation that the current variant was actually tested in those papers rather than relying on the table's generic calibration.
• The exact c.7243G>C / p.Ala2415Pro row in Sun et al. Table S1 is classified Non-functional with Medium-high confidence and DeepATM_predicted=No, indicating a direct prime-editing screen measurement rather than a model extrapolation.
• CHECKLIST ps3_1: Is the evidence a well-established in vitro or in vivo functional study supportive of a damaging effect on the gene or gene product? — TRUE — The exact variant has a direct prime-editing functional-screen result classified as Non-functional, although the assay is not among the ATM VCEP-calibrated assays.
• CHECKLIST ps3_2: Has the functional study been validated and shown to be reproducible and robust in a clinical diagnostic laboratory setting? — NA — No clinical-diagnostic-laboratory validation or reproducibility evidence was provided in the case bundle.
• CHECKLIST ps3_3: Is the evidence phenotypic evidence (e.g. a lack of ATM activity in cells from an Ataxia-Telangiectasia patient), which must not be used as functional data? — FALSE — The available functional result is a direct engineered-cell prime-editing screen, not a patient phenotypic assay.
• CHECKLIST ps3_4: For protein evidence, have the detailed notes on ATM-specific assays been consulted? — TRUE — The ATM VCEP-specific kinase-activity and radiosensitivity assay guidance was reviewed.
• CHECKLIST ps3_5: For RNA evidence, has PVS1_Strength(RNA) been used and has strength been modulated based on assay quality and quantity (curator discretion)? — NA — This is a missense variant with direct prime-editing functional evidence, not an RNA assay.
• CHECKLIST ps3_6: Does the variant fail to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity? — NA — The bundle does not provide variant-specific ATM-substrate phosphorylation and radiosensitivity readouts for this variant.
• CHECKLIST ps3_7: Does the variant fail to rescue an ATM specifc feature only (e.g. phosphorylation of ATM-specific targets)? — NA — The bundle does not provide a variant-specific ATM-specific feature readout such as phosphorylation of ATM targets.
• CHECKLIST ps3_8: Is the evidence radiosensitivity-only, which must not be used because it is not a feature specific to ATM deficiency? — FALSE — The evidence is a prime-editing functional screen, not a radiosensitivity-only result.
• CHECKLIST ps3_9: Has PS3 been prevented from use at strong strength? — TRUE — The VCEP instruction explicitly states not to use PS3 as strong, and no strong strength was assigned.

Still missing

• No evidence was found that the direct prime-editing assay has been validated as reproducible and robust in a clinical diagnostic laboratory setting.
• The Sun et al. assay does not report the ATM-specific phosphorylation readout and radiosensitivity combination required by the ATM VCEP calibration, so it is not established whether the variant fails both required features or an ATM-specific feature alone.
• Human adjudication is needed to determine whether the directly measured but non-VCEP-calibrated prime-editing result can support PS3 under ATM VCEP v1.5.

Sources

Reasoning

The ATM HBOP VCEP permits PS4 only from case-control evidence meeting p-value ≤0.05 plus an odds ratio, hazard ratio, or relative risk ≥2 (or lower 95% CI ≥1.5). No exact-variant case-control enrichment data were identified. The only reviewed publication reports gene-level ATM mutation frequencies in familial pancreatic cancer and explicitly does not mention c.7243G>C (p.Ala2415Pro); it cannot establish variant-specific enrichment.

Rule

ATM HBOP VCEP v1.5 PS4 Strong: case-control p-value ≤0.05 and OR/HR/RR ≥2 or lower 95% CI ≥1.5.

Evidence considered

• ATM HBOP VCEP v1.5 specifies PS4 Strong as a case-control study with p-value ≤0.05 and odds ratio, hazard ratio, or relative risk ≥2, or lower 95% confidence interval ≥1.5; it does not permit PS4_Moderate for this gene.
• PMID:25394175 was reviewed for c.7243G>C and p.(A2415P) and does not report the variant. Its quoted ATM frequencies concern unspecified ATM mutations in familial pancreatic cancer, not variant-specific case-control enrichment.

Still missing

• A case-control study reporting c.7243G>C (p.Ala2415Pro) counts in affected individuals and controls, with an effect estimate and statistical significance.

Sources

Reasoning

The ClinGen HBOP ATM VCEP v1.5 PM3/BP2 points-based framework applies, but the case bundle contains no affected-proband phenotype, second pathogenic/likely pathogenic ATM variant, zygosity, or parent/offspring phase data. Therefore no PM3 points or strength can be assigned.

Rule

ATM VCEP v1.5: PM3_VeryStrong >= 8 points; PM3_Strong = 4 points; PM3 = 2 points; PM3_Supporting = 1 point, using the ATM PM3/BP2 table.

Evidence considered

• The governing source is the ClinGen HBOP ATM VCEP v1.5 specification, which directs use of the ATM PM3/BP2 points table for A-T and assigns final PM3 strength from the summed PM3 points.
• The ATM PM3/BP2 table assigns points according to affected-proband phenotype, zygosity, the presence and classification of the second allele, and whether trans phase is confirmed; none of those case-specific observations are present in the consolidated evidence bundle.
• CHECKLIST pm3_1: Has the ATM PM3/BP2 table been consulted to determine the points assigned for this proband and the final PM3 code assignment from the sum of PM3-related points? — TRUE — The bundle contains and identifies the ATM PM3/BP2 VCEP v1.5 points table and its PM3 strength thresholds, but no case points can be assigned.
• CHECKLIST pm3_2: Does the proband have Ataxia Telangiectasia (A-T), including consideration of the ‘variant’ or ‘atypical’ A-T exceptions in which phenotypes are more mild with slower progression? — NA — No proband phenotype, A-T diagnosis, or atypical/variant A-T information is documented.
• CHECKLIST pm3_3: Is the variant detected in trans with a pathogenic variant for this recessive disorder? — NA — No second ATM variant or trans observation is documented.
• CHECKLIST pm3_4: Has phase been determined by testing parents or offspring? — NA — No parental or offspring testing and no phase result are documented.
• CHECKLIST pm3_5: Does the sum of PM3-related points meet one of the stated final assignment thresholds: PM3_VeryStrong ≥ 8 points, PM3_Strong = 4 points, PM3 = 2 points, or PM3_Supporting = 1 point? — NA — The PM3 point sum cannot be calculated because the required proband, allele, and phase data are missing.

Still missing

• Affected-proband A-T phenotype and diagnosis status are not documented.
• A pathogenic or likely pathogenic ATM allele in trans is not documented.
• Zygosity and phase testing by parents or offspring are not documented.
• The per-proband PM3 point total cannot be calculated without the missing clinical, allelic, and phase observations.

Sources

Reasoning

The ClinGen HBOP ATM VCEP v1.5 BP2 points-based framework applies, but the case bundle contains no unaffected-individual observation, ATM allele in trans, dominant-gene comparator in trans, cis pathogenic variant, zygosity, age, or A-T phenotype information. Therefore no BP2 points or strength can be assigned.

Rule

ATM VCEP v1.5: BP2_Strong <= -4 points; BP2_Moderate = -2 points; BP2 = -1 point, using the ATM PM3/BP2 table.

Evidence considered

• The governing source is the ClinGen HBOP ATM VCEP v1.5 specification, which directs use of the ATM PM3/BP2 points table for BP2 and assigns final BP2 strength from the summed BP2 points.
• The ATM PM3/BP2 table requires specific unaffected-individual, zygosity, trans/cis, inheritance, and age/phenotype observations for BP2; none of those case-specific observations are present in the consolidated evidence bundle.
• CHECKLIST bp2_1: Has the ATM PM3/BP2 table been consulted to determine the points assigned for this proband and the final BP2 code assignment from the sum of BP2-related points? — TRUE — The bundle contains and identifies the ATM PM3/BP2 VCEP v1.5 points table and its BP2 strength thresholds, but no case points can be assigned.
• CHECKLIST bp2_2: Is the individual homozygous or does the individual have the variant in trans with a likely pathogenic or pathogenic ATM variant for possible downgrade? — NA — Zygosity and any second ATM allele or its classification are not documented.
• CHECKLIST bp2_3: If assessing a homozygous or in trans variant for possible downgrade in an unaffected individual, is the individual 18 years or older with no evidence of A-T? — NA — Unaffected status, age, zygosity/phase, and evidence regarding A-T are not documented.
• CHECKLIST bp2_4: Is the variant 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? — NA — No trans dominant-gene observation, cis pathogenic variant, or phase data are documented.
• CHECKLIST bp2_5: Does the sum of BP2-related points meet one of the stated final assignment thresholds: BP2_Strong ≤ -4 points, BP2_Moderate = -2 points, or BP2 = -1 point? — NA — The BP2 point sum cannot be calculated because the required unaffected-individual, zygosity, phase, age, and comparator-variant data are missing.

Still missing

• An unaffected individual carrying the variant with a pathogenic or likely pathogenic ATM variant in trans is not documented.
• The individual's zygosity, age, A-T status, and whether the observation is from a laboratory or database setting are not documented.
• A pathogenic variant in a fully penetrant dominant gene in trans or a pathogenic variant in cis is not documented.
• The per-individual BP2 point total cannot be calculated without the missing allelic, inheritance, and clinical observations.

Sources