Five-step scale from benign to pathogenic. This variant is pathogenic. Select a step to read what it means.
This variantScenario
BenignPathogenic
Pathogenic.A pathogenic classification under the recorded framework.
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.
Met (Very Strong): stop-gain at residue 1858 is a null allele predicted to trigger nonsense-mediated decay, removing the C-terminal kinase region.
PM2Supporting
PM2 · supporting
Met (Supporting): absent from gnomAD v4.1, v2.1, and Canada (AF = 0), far below the ≤0.001% threshold.
PM3Moderate
PM3 · moderate
Met (Moderate): one unrelated A-T proband (AT35RM) with a confident phenotype carries the variant with a second truncating ATM allele, phase unknown (2.0 points).
PM5Supporting
PM5 · supporting
Met (Supporting): the premature stop at residue 1858 lies upstream of the VCEP truncation cutoff p.Arg3047.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Pathogenic
Pathogenic: under the ClinGen HBOP ATM VCEP v1.5, PVS1 (very strong) with PM2 and PM5 (supporting) satisfies Rule 4 (≥1 very strong + ≥2 supporting); PM3 (moderate) adds further support.
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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
ACMG/AMP criteria under ClinGen ATM VCEP v1.5, with the data and sources behind each one.
28 criteria with recorded statuses: 4 met · 5 not met · 3 not assessed · 16 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Governing framework: ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985). PVS1 is adjudicated via the ATM PVS1 Decision Tree; PM4 is restricted by the VCEP to stop-loss variants; BP3 is declared Not Applicable by the VCEP.
Variant consequence: NM_000051.4:c.5574G>A is a nonsense SNV producing NP_000042.3:p.(Trp1858Ter) (Mutalyzer-normalized; predicted protein terminates at residue 1858 vs 3057 in reference). SpliceAI max delta = 0.01 excludes a splice-altering effect, so the variant is a pure null allele.
PVS1 met at Very Strong: null (nonsense) variant in ATM, a gene with established LOF disease mechanism (pvs1_gene_gate 'eligible'); PTC in an internal exon ~70 nt upstream of the next exon-exon junction with ~3.6 kb of CDS remaining downstream, well upstream of the VCEP truncation boundary p.Arg3047, so NMD is predicted; not an extreme-3'-end allele; truncation removes ~1,200 C-terminal residues including the FAT/PI3-K/FATC kinase region (treated as one contiguous domain per the VCEP, PMID 28508083).
PM4 not applicable: the VCEP v1.5 rule 'Use for stop-loss variants' does not cover stop-gain/nonsense changes; the null consequence is captured by PVS1.
BP3 not applicable: declared Not Applicable by the ATM HBOP VCEP v1.5; the variant is not an in-frame indel in a repeat region.
No retrieved publication mentions c.5574G>A/p.Trp1858Ter (all six full texts searched); no criterion in this group is inferred from ClinVar's Pathogenic classification or from any other source's final classification.
Governing framework: ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer (HBOP) ATM VCEP v1.5 (CSpec 639508985), applied in preference to generic ACMG/AMP (generic rules consulted only where the VCEP is silent; none needed for this group).
Variant under assessment: NM_000051.4:c.5574G>A = NP_000042.3:p.(Trp1858Ter), a nonsense/stop-gain (null) variant with no predicted splice impact (SpliceAI max delta 0.01).
PS1: not applicable - the ATM VCEP PS1 standard path requires a missense same-amino-acid change and the splicing-table path requires a predicted splice event matching a reference P/LP variant; this is a nonsense variant with SpliceAI 0.01, and no alternate-nucleotide same-stop comparator (e.g., c.5573G>A) is documented.
PM1, PP2, BP1: not applicable - all three are explicitly declared 'Not Applicable' in ATM VCEP v1.5; the variant is also not missense and not in a Cancer Hotspots hotspot (no result for ATM W1858).
PM5: met at Supporting - ATM VCEP v1.5 PM5 rule applies to frameshifting/truncating variants with premature termination codons upstream of p.Arg3047; p.Trp1858Ter carries its PTC at residue 1858 (upstream of 3047). Corroborated as a null allele by yeast stop-codon assay (PMID 12105990) and absent ATM protein in patient AT35RM (PMID 10864201).
No hotspot, domain, or same-residue alternate-variant evidence (PS1/PM1 inputs) exists for this variant in the evidence bundle; citations were grounded to exact-variant mentions only.
Governing framework: ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985, precedence_rank 1, framework_mode criteria_combination). It explicitly declares PS2, PM6 and BS4 Not Applicable, and specifies PP1 under autosomal-recessive conditions (1 affected relative = Supporting, 2 = Moderate, >=3 = Strong).
Variant: ATM c.5574G>A (p.Trp1858Ter), a nonsense variant. Proband-level evidence exists (AT patient cell line AT35RM, compound heterozygous with c.3576G>A, reported in PMID 10864201 and PMID 12105990), but all four criteria in this group (de novo and segregation) require family-level data.
The complete case evidence bundle contains no de novo occurrence, parental testing, meioses, segregation, or non-segregation data for c.5574G>A. The two AT cohort papers cited by the ClinVar submitter (PMID 23807571, PMID 25614872) were reviewed in full text and neither reports this variant among its mutations.
Group conclusion: PS2 not_applicable (VCEP), PM6 not_applicable (VCEP), BS4 not_applicable (VCEP), PP1 not_assessed (no affected-relative segregation data; gap identified). This group contributes no met evidence to the classification.
Both PS3 and BS3 are not_assessed: no variant-specific functional assay result exists in the case evidence bundle for NM_000051.4:c.5574G>A (p.Trp1858Ter).
The VCEP-approved PS3/BS3 assays (vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1: Mitui 2009, Barone 2009, Scott 2002) are calibration-only and none of those papers was retrieved for this case; testing of p.Trp1858Ter in them could not be confirmed.
The only variant-specific functional-screen entry (Sun et al. 2025 Table S1, vcep_suppl_tables1_pmid_40580951) for c.5574G>A is DeepATM_predicted=Yes / Confidence='Computational prediction' ('Non-functional' classification), which the VCEP index guidance explicitly excludes from functional evidence; it was therefore not used for PS3 or BS3.
None of the retrieved full texts (PMID:10864201, PMID:12105990, PMID:23807571, PMID:25614872) mentions the variant; no functional weight can be derived from them.
needs_human_review is set for PS3 and BS3 per VCEP index guidance (flag when the Sun et al. table is the only PS3/BS3 evidence for a variant) and because the three approved-assay papers could not be checked for testing of this variant.
PS4 not_met: The HBOP ATM VCEP v1.5 PS4 rule requires a case-control study with p-value ≤0.05 AND (OR/HR/RR ≥2 OR lower 95% CI ≥1.5). No case-control study of c.5574G>A exists in the evidence bundle; the variant is present only as case observations (A-T patient cell line AT35RM in PMID:10864201 and PMID:12105990) and a single-laboratory ClinVar Pathogenic assertion, none of which provides case-control enrichment statistics.
PP4 not_applicable: VCEP v1.5 marks PP4 Not Applicable; A-T phenotype specificity is instead scored through the PM3/BP2 phenotype-confidence (confident/consistent) points system.
PP5 not_applicable: VCEP v1.5 marks PP5 Not Applicable, and the exact-variant ClinVar record is a 1-star single-laboratory (Labcorp/Invitae) Pathogenic submission with no expert-panel classification, so the global expert-panel PP5 trigger is not satisfied.
BP5 not_applicable: VCEP v1.5 marks BP5 Not Applicable, and no alternate molecular basis for disease has been reported for this variant.
BP6 not_applicable: VCEP v1.5 marks BP6 Not Applicable, and no expert-panel Benign/Likely benign classification exists for the exact variant (ClinVar is Pathogenic, single laboratory).
PM3: met (Moderate). 2.0 points from one unrelated A-T proband (AT35RM, PMID:10864201), confident phenotype, compound heterozygous c.5574G>A with truncating c.3576G>A, phase unknown (no parental genotyping documented); ATM VCEP v1.5 maps 2.0 points to PM3 Moderate.
BP2: not met. No unaffected (non-A-T) adult with c.5574G>A in trans with a P/LP ATM variant in any source; gnomAD AF = 0; the only germline observation is an affected proband (counted under PM3).
PP3 not_met: nonsense variant; SpliceAI max delta 0.01 is far below the ATM VCEP v1.5 PP3 splicing threshold (>=0.2), the missense sub-path (REVEL >0.7333) is inapplicable to a nonsense variant, and REVEL is unavailable; BayesDel 0.652534 is unusable (no verified published threshold); Sun et al. 2025 computational scores (CADD 42, boostDM 0.99, DeepATM_predicted=Yes) are model extrapolation with no VCEP-calibrated threshold.
BP4 not_applicable: no applicable VCEP sub-path for a nonsense variant - missense path (REVEL <=0.249) inapplicable and REVEL NA; splicing path (SpliceAI <=0.1) excluded by the lab curator override because splicing is not the primary plausible mechanism for a truncating variant. Explicitly noted: the override changes the outcome from the literal VCEP text, which would have met BP4.
BP7 not_applicable: BP7 is scoped to synonymous and deep intronic variants; c.5574G>A is an exonic nonsense variant, and no RNA data (BP7(RNA)) exists in the bundle.
No computational criterion from this group contributes supporting evidence in either direction; the variant's damaging effect is a protein-truncation mechanism evaluated by other groups (PVS1). No prediction is double-counted across PP3/BP4/BP7.
Governing framework: ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985); all population criteria were adjudicated against its gnomAD v4-based thresholds (BA1 >0.5%, BS1 >0.05%, PM2 <=0.001%).
The variant NM_000051.4:c.5574G>A (p.Trp1858Ter, a nonsense/loss-of-function change) is absent from gnomAD v4.1, gnomAD v2.1, and gnomAD-Canada v1.0 (AF = 0 in every queried dataset).
BA1 not met: gnomAD v4 AF of 0% is below the VCEP BA1 threshold of 0.5%.
BS1 not met: gnomAD v4 AF of 0% is below the VCEP BS1 threshold of 0.05%.
BS2 not applicable: declared Not Applicable by the ATM HBOP VCEP v1.5.
PM2 met at Supporting strength: AF of 0% satisfies the VCEP <=0.001% rarity threshold; absence of the allele across large population cohorts, with no homozygotes, is consistent with a pathogenic loss-of-function allele.
No population-frequency evidence supports any benign criterion for this variant.
No criteria match.
Met · 4
PVS1Very strongMet (Very Strong): stop-gain at residue 1858 is a null allele predicted to trigger nonsense-mediated decay, removing the C-terminal kinase region.
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Reasoning
Governing framework is the ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985), whose PVS1 rule states 'Use ATM PVS1 Decision Tree' (Very Strong default), implemented in the ATM PVS1 v1.5 decision guide (adapted from PMID 30192042). The ATM VCEP PVS1 gene gate is satisfied: pvs1_gene_context.json reports lof_mechanism_supported=true (official CSPEC/VCEP PVS1 guidance exists for ATM) and pvs1_gene_gate='eligible'. Variant consequence: NM_000051.4:c.5574G>A is a nonsense SNV, Mutalyzer-normalized to NP_000042.3:p.(Trp1858Ter) (position_first 1857, position_last_predicted 1858, i.e. the predicted protein terminates at residue 1858 versus 3057 in the reference); consequence_class 'nonsense' per pvs1_variant_assessment.json. This is a null variant under the VCEP decision tree (nonsense is an explicitly listed null class) with no alternative mechanism: SpliceAI max delta = 0.01 rules out a splice-altering effect, and the variant is not at a canonical +/-1,2 splice site. NMD and 3'-end assessment: the PTC lies in an internal exon, ~70 nt upstream of the next exon-exon junction (exon [c.5470-5646]; the CDS continues ~3.6 kb downstream), so it is far from the terminal exon and is predicted to trigger NMD; it is also well upstream of the VCEP's own truncation boundary p.Arg3047 (referenced in the PM5 rule for frameshifting/truncating variants), which the VCEP uses to identify NMD-prone truncations. This is not an 'extreme 3' end of gene' variant, so the VCEP PVS1 caveat #1 does not apply, and the variant is a SNV, so the in-frame-exon-skipping caveat #2 does not apply. Transcript relevance is confirmed: the VCEP default transcript is NM_000051.3/ENST00000278616.8 and the variant is annotated on NM_000051.4, which shares an identical CDS (Mutalyzer resolved the change on NP_000042.3 without shift or warning); no population LoF enrichment concern applies (variant absent from gnomAD v2.1/v4.1/Canada). Functional-importance context: the truncation removes ~1,200 C-terminal residues, including the C-terminal FAT/PI3-K/FATC kinase region that the VCEP explicitly treats as one contiguous functional domain (PMID 28508083), so the affected region is biologically critical rather than a dispensable distal tail. Accordingly, full-strength PVS1 (Very Strong) is applied per the ATM VCEP v1.5 decision tree. No retrieved publication mentions this exact variant, so PVS1 rests on the predicted null consequence and NMD position rules rather than on published RNA/functional confirmation of the allele itself.
Rule
PVS1 (Very Strong): Use ATM PVS1 Decision Tree - null variant (nonsense) in a gene with established LOF mechanism; NMD-prone (PTC upstream of p.Arg3047, internal exon, not extreme 3' end) (ClinGen HBOP ATM VCEP v1.5)
Evidence considered
ClinGen HBOP ATM VCEP v1.5 (cspec, doc 639508985) PVS1 rule: 'Use ATM PVS1 Decision Tree' with Very Strong as default strength
ATM PVS1 v1.5 decision guide (vcep_atm_pvs1_1_5, adapted from PMID 30192042): null variant classes include nonsense; caveats are (1) extreme 3' end of gene and (2) splice variants causing in-frame exon skipping leaving the remainder intact - neither applies to this nonsense SNV in an internal exon; FAT, PI3-K, FATC treated as one contiguous domain (PMID 28508083)
pvs1_gene_context: ATM germline LOF is an established disease mechanism (official CSPEC/VCEP PVS1 guidance present); pvs1_gene_gate = 'eligible'
pvs1_variant_assessment: consequence_class 'nonsense', protein p.(W1858*), variant_bucket 'nonsense', suggested_default_strength 'PVS1'
pvs1_generic_framework (ClinGen SVI PVS1 recommendations, PMC6185798 / PMID 30192042): nonsense variants with PTC >50 nt upstream of the final exon-exon junction are expected to undergo NMD; here the PTC is ~70 nt upstream of the next junction with many junctions downstream
spliceai (registry key spliceai): max delta score 0.01, no predicted splice impact - the variant acts as a pure nonsense/null allele
Still missing
No RNA/NMD or protein-expression study of this exact allele (c.5574G>A/p.Trp1858Ter) is present in the retrieved literature (none of the six full-text papers mentions the variant); NMD is inferred from the VCEP decision-tree position rules (internal exon, PTC >50 nt upstream of the downstream exon-exon junction, upstream of p.Arg3047). An RNA assay confirming NMD would convert the prediction into direct evidence.
The variant is annotated on NM_000051.4 while the ATM VCEP v1.5 default transcript is NM_000051.3; the CDS is identical and Mutalyzer confirmed p.Trp1858Ter, so transcript relevance is not in doubt, but the transcript-version mismatch should be noted in any submission.
PM2SupportingMet (Supporting): absent from gnomAD v4.1, v2.1, and Canada (AF = 0), far below the ≤0.001% threshold.
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Reasoning
ClinGen HBOP ATM VCEP v1.5 PM2 rule: frequency <=0.001% in gnomAD v4 dataset, with PM2_Supporting explicitly named (and a single allele in one subpopulation already treated as sufficiently rare). The variant is absent from gnomAD v4.1 (0 alleles, AF = 0, no homozygotes) and also absent from gnomAD v2.1 and gnomAD-Canada v1.0, so the frequency is well below 0.001%. PM2 is met at Supporting strength. Note: CSPEC lists PM2 defaultStrength as 'Pathogenic Moderate', but the operative rule text specifies PM2_Supporting at this frequency (consistent with the ClinGen SVI PM2_Supporting calibration); Supporting is applied per the rule text.
Rule
PM2 (Supporting): Frequency <=0.001% in gnomAD v4 dataset (ClinGen HBOP ATM VCEP v1.5)
PM3ModerateMet (Moderate): one unrelated A-T proband (AT35RM) with a confident phenotype carries the variant with a second truncating ATM allele, phase unknown (2.0 points).
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Reasoning
ClinGen HBOP ATM VCEP v1.5 applies (cspec doc 639508985; ATM_PM3_BP2_1.5.pdf). One unrelated A-T proband is documented: AT35RM in Delia et al. 2000 (PMID:10864201), Table 1, a compound heterozygote for c.3576G>A and c.5574G>A, both nonsense mutations predicted to truncate ATM. Phenotype is 'confident': the study's cohort is clinically diagnosed A-T (VCEP: publications claiming a clinical diagnosis of A-T are taken at face value and granted a confident diagnosis), and ATM protein was <2% of control (densitometry 0.02 vs normal LBC-N), satisfying VCEP Laboratory result #1 (ATM protein <=15% of controls). Phase of the two alleles is NOT confirmed: no parental genotyping of the 3576G>A/5574G>A alleles is reported (the paper's segregation analyses identified heterozygous relatives for other families only), and the VCEP stipulation allowing assumed-in-trans (VUA seen with >=2 different P/LP variants) is not met with a single co-occurring variant. Per the ATM PM3/BP2 table: confident phenotype, phase unknown = 2.0 points per unrelated A-T proband -> PM3 Moderate (2.0 points). The co-occurring c.3576G>A (p.Trp1192Ter) is a truncating nonsense variant and is assumed P/LP under VCEP LOF rules, but was not independently re-classified under VCEP v1.5 in this case. The same proband (AT35RM) is re-described in Tsuchida et al. 2002 (PMID:12105990) and is counted ONCE; M059J (same paper) is a somatic glioblastoma cell line and contributes no germline evidence. Variant is absent from gnomAD v2.1, v4.1 and gnomAD-Canada (AF=0), satisfying the VCEP PM3 population-frequency ceiling (>0.01%). If a curator judged the phenotype 'consistent' instead of 'confident', points would be 1.0 (PM3_Supporting); if phase were confirmed in trans, points would be 4.0 (PM3_Strong).
Rule
PM3 = 2 points (Moderate). ClinGen HBOP ATM VCEP v1.5 PM3/BP2 table (ATM_PM3_BP2_1.5.pdf; cspec doc 639508985): points per unrelated A-T proband - Phenotype confident, phase unknown = 2.0; PM3 Moderate = 2.0 points. Multiple unrelated cases are additive; VUA must not exceed general population frequency >0.01%.
Evidence considered
PMID:10864201 - Table 1, case AT35RM: '3576 GA / 5574 GA', ATM protein <0.02 of control; one unrelated A-T proband, confident phenotype, compound heterozygous with phase unknown -> 2.0 points toward PM3.
PMID:12105990 - confirms AT35RM is the same single AT patient-derived LCL compound heterozygous for 3576 G->A / 5574 G->A; M059J glioblastoma line is somatic and not counted; no additional unrelated probands or unaffected carriers.
gnomad_v2 / gnomad_v4 / gnomad_canada - variant absent (AF=0), satisfies VCEP PM3 general consideration that the variant not exceed 0.01% general population frequency.
Still missing
Phase (trans vs cis) for AT35RM not experimentally confirmed - no parental genotyping of c.3576G>A / c.5574G>A documented in PMID:10864201; only the phase-unknown column (2.0 points) is used.
Co-occurring c.3576G>A (p.Trp1192Ter) assumed P/LP from its truncating nature; VCEP requires co-occurrent P/LP variants to be classified under VCEP specifications - not independently re-classified in this case.
PMID:23807571 (Huang 2013, Chinese A-T cohort) full-text retrieval returned an empty file; the variant could not be verified there. ClinVar lists this paper for c.5574G>A, so additional unrelated probands (1.0-4.0 points) may exist - needs human review of the original paper.
Phenotype confidence for AT35RM rests on the VCEP 'clinical diagnosis of A-T taken at face value' clause plus one laboratory result (ATM protein <2%); if judged 'consistent', points drop to 1.0 (PM3_Supporting).
Only one unrelated proband identified; PM3 strength cannot be raised beyond Moderate without additional verified probands.
PM5SupportingMet (Supporting): the premature stop at residue 1858 lies upstream of the VCEP truncation cutoff p.Arg3047.
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Reasoning
Under the governing ClinGen HBOP ATM VCEP v1.5 (CSpec 639508985), PM5 is a gene-specific truncation-cutoff rule (not the classic same-residue missense PM5): it applies at Supporting strength to 'frameshifting or truncating variants with premature termination codons upstream of p.Arg3047' (and to splice variants with NMD-prone PTCs upstream of p.Arg3047 where PVS1_VS(RNA) is applied). The variant under assessment, NM_000051.4:c.5574G>A, is a nonsense/truncating change p.(Trp1858Ter): the premature termination codon is at residue 1858, which is upstream of p.Arg3047 (1858 < 3047), so the rule is satisfied. The truncating/null nature of the allele is corroborated by a yeast frameshift/stop-codon assay reporting that the 5574 G>A allele (patient AT35RM) yields ~48.9% Ura+ colonies versus ~97% wild-type, consistent with a premature stop (PMID 12105990), and by near-absent ATM protein in AT35RM cells (protein level <0.02; PMID 10864201, Table 1). Both papers report the variant under legacy ATM cDNA numbering ('5574 G→A'), mapped to NM_000051.4:c.5574G>A via the ClinVar exact-match validated PMID trail (SCV002154400). The PTC at residue 1858 is well upstream of the extreme 3' end, so the PVS1-guide 3'-end caution does not affect this assessment. Note: this VCEP's PM5 is a truncation-cutoff rule; classic same-residue missense PM5 does not apply to this nonsense variant, and no alternate missense at codon 1858 (e.g., p.Trp1858Cys from c.5574G>T/G>C) is documented in the evidence bundle.
Rule
ATM VCEP v1.5 PM5 (Supporting): 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047.'
Evidence considered
ATM VCEP v1.5 (CSpec 639508985) PM5 rule: 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047' (Supporting strength).
Variant annotation: NP_000042.3:p.(Trp1858Ter) - nonsense/truncating; PTC at residue 1858, upstream of p.Arg3047 (ClinVar VCV001380184; Mutalyzer/VariantValidator normalization).
PMID 12105990 (Tsuchida et al. 2002): yeast frameshift/stop-codon assay - heterozygous '5574 G→A' allele in AT35RM gives 48.9 +/- 17.5% Ura+ colonies vs ~97% wild-type, indicating a premature stop codon in the allele.
PMID 10864201 (Delia et al. 2000): AT35RM carries '3576 G→A / 5574 G→A' with essentially absent ATM protein (level <0.02), consistent with a null/truncating allele.
Positional check: residue 1858 is well upstream of the p.Arg3047 cutoff and of the extreme 3' end of ATM (protein 3056 aa); no 3'-end caution applies.
Still missing
None for the truncation-cutoff PM5 rule: p.Trp1858Ter has a PTC (residue 1858) upstream of p.Arg3047. If a classic same-residue missense PM5 framework were ever applied, alternate missense changes at codon 1858 (e.g., c.5574G>T/G>C, p.Trp1858Cys) are not documented in this case's evidence bundle and would need collection.
PS4Not met: no case-control study of this variant exists; only case observations without a p-value or odds ratio are documented.
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Reasoning
Governing framework is the ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985), which defines PS4 strictly as: 'Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5)'. No case-control study of c.5574G>A (p.Trp1858Ter) exists anywhere in the evidence bundle. The variant is documented only as case observations: A-T patient-derived cell line AT35RM carries 3576 G→A / 5574 G→A with essentially undetectable ATM protein (PMID:10864201, Table 1), and the same 5574 G→A allele is validated as truncating by a yeast frameshift/stop-codon assay (PMID:12105990). The ClinVar record (VCV001380184) is a Pathogenic assertion by a single clinical laboratory (1 star), which is not case-control enrichment evidence. None of these sources provides an OR/HR/RR with confidence interval or a p-value, so the VCEP PS4 rule is not satisfied.
Rule
Case-control studies; p-value ≤.05 AND (Odds ratio, hazard ratio, or relative risk ≥2 OR lower 95% CI ≥1.5). (HBOP ATM VCEP v1.5, cspec doc 639508985)
Evidence considered
HBOP ATM VCEP v1.5 PS4 rule (cspec): case-control studies; p-value ≤0.05 AND (OR/HR/RR ≥2 OR lower 95% CI ≥1.5) - no case-control study located, so the rule cannot be met.
PMID:10864201 (Delia 2000), Table 1, case AT35RM: '3576 GA / 5574 GA' with ATM protein level <0.02 (essentially absent) - case observation in an A-T patient-derived cell line; no case-control statistics.
PMID:12105990 (Tsuchida 2002): yeast frameshift/stop-codon assay shows the 5574 G→A allele of AT35RM is truncating (48.9 ± 17.5% Ura1 colonies in fragment c) - functional/case observation; no case-control data.
ClinVar VCV001380184: Pathogenic, 1 clinical laboratory (Labcorp Genetics/Invitae, SCV002154400), review status 'criteria provided, single submitter' (1 star) - laboratory assertion, not case-control enrichment.
Still missing
No case-control study (with odds ratio/hazard ratio/relative risk, 95% CI, and p-value ≤0.05) for c.5574G>A in any phenotype cohort (A-T, ATM-related cancer predisposition, or other) is available in the evidence bundle.
PP3Not met: SpliceAI max delta 0.01 is well below the 0.2 splicing threshold, and the missense sub-path does not apply to a nonsense variant.
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Reasoning
Variant is a nonsense change, NM_000051.4:c.5574G>A, p.(Trp1858Ter) (consequence_class=nonsense), so the VCEP PP3 missense sub-path (REVEL >0.7333) is not applicable, and the VCEP PP3 splicing sub-path (SpliceAI >=0.2 for silent, missense/in-frame and intronic variants outside donor/acceptor +/-1,2) does not enumerate nonsense variants. Evaluating the splice path anyway for completeness: SpliceAI max delta score = 0.01 (DS_AG 0.01; DS_AL/DS_DG/DS_DL 0.0), well below the 0.2 threshold -> no predicted splice impact, PP3 not met. REVEL is unavailable for this variant (pipeline lookup not found; Sun et al. 2025 Table S1 row for c.5574G>A also REVEL=NA), and the missense sub-path would not apply to a nonsense variant regardless. BayesDel score 0.652534 was retrieved but is treated as insufficiently calibrated (no verified published threshold nameable for this pipeline) and is in any case not part of the VCEP PP3 rule. Sun et al. 2025 Table S1 reports CADD phred 42 and boostDM 0.991 with DeepATM_predicted=Yes (Confidence='Computational prediction'), i.e. the 'Non-functional' classification is model extrapolation, not a functional measurement, and no VCEP-calibrated PP3 threshold exists for CADD/boostDM; therefore it confers no PP3. Secondary computational signals pointing to loss-of-function are consistent with the truncating mechanism already captured by PVS1 (another group) and are not double-counted here.
Rule
ATM VCEP v1.5 PP3: Missense REVEL >0.7333; Splicing: predicted impact via splicing (SpliceAI >=0.2) for silent, missense/in-frame and intronic variants outside donor and acceptor 1,2 sites.
Evidence considered
spliceai: SpliceAI max delta score 0.01 for NM_000051.4:c.5574G>A (11-108175479-G-A, GRCh37) - below ATM VCEP v1.5 PP3 splicing threshold of >=0.2
REVEL score not available for this variant (pipeline lookup and Sun et al. 2025 Table S1 both report NA); because the variant is nonsense the missense sub-path is inapplicable, so this gap does not change the outcome.
No VCEP-calibrated threshold exists for CADD/boostDM/AlphaMissense, so the Sun et al. 2025 computational scores cannot be mapped to a PP3 strength.
SpliceAI is the only splice predictor available; no RNA-based splice assay data for this variant is present in the case bundle (would belong to PVS1_RNA/BP7(RNA) review rather than PP3).
BA1Not met: allele frequency 0 (absent from gnomAD v4.1) is far below the >0.5% BA1 threshold.
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Reasoning
Governing framework is the ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985), which defines BA1 as Grpmax filtering AF >0.5% in gnomAD v4 (Stand Alone). The variant NM_000051.4:c.5574G>A (p.Trp1858Ter) is absent from gnomAD v4.1 (chr11-108304752-G-A, GRCh38; lookup search_status 'absent', observed AF = 0) and is also absent from gnomAD v2.1 and gnomAD-Canada v1.0. An AF of 0% is far below the 0.5% BA1 threshold, so BA1 is not met.
Rule
BA1 (Stand Alone): Grpmax Filtering AF >0.5% in gnomAD v4 dataset (ClinGen HBOP ATM VCEP v1.5)
BS1Not met: allele frequency 0 (absent from gnomAD v4.1) is below the >0.05% BS1 threshold.
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Reasoning
Governing framework is the ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985), which defines BS1 as Grpmax filtering AF >0.05% in gnomAD v4 (Strong). The variant is absent from gnomAD v4.1 (AF = 0; also absent from gnomAD v2.1 and gnomAD-Canada v1.0), so the AF is below the 0.05% BS1 threshold. BS1 is not met.
Rule
BS1 (Strong): Grpmax Filtering AF >0.05% in gnomAD v4 dataset (ClinGen HBOP ATM VCEP v1.5)
BP2Not met: no unaffected adult carrier of the variant with a second P/LP ATM allele is documented (0 BP2 points).
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Reasoning
Under ClinGen HBOP ATM VCEP v1.5, BP2 points accrue only for unaffected (non-A-T) adults (>18y, no evidence of A-T) carrying the VUA together with a P/LP ATM variant in trans: -4.0 (confirmed trans) / -2.0 (phase unknown) / -2.0 lab setting or -1.0 database setting (homozygous, max -2.0); BP2 Supporting = -1.0, Moderate = -2.0, Strong <= -4.0. No such observation exists for c.5574G>A in any source: the variant is absent from gnomAD v2.1, v4.1 and gnomAD-Canada (AF=0, no population carriers or homozygotes); the only germline observation in the literature is affected A-T proband AT35RM (PMID:10864201), which supports PM3 rather than BP2; the M059J cell line (PMID:12105990) is a somatic glioblastoma line, not an unaffected individual; and the single ClinVar germline submission (Labcorp, SCV002154400) contains no unaffected-carrier or in-trans co-occurrence data (its Pathogenic label is not used as evidence). For a truncating nonsense VUA, an unaffected adult compound heterozygote with a second P/LP variant would in any case not be expected. Total BP2 points = 0 -> not met.
Rule
BP2 per ClinGen HBOP ATM VCEP v1.5 PM3/BP2 table (ATM_PM3_BP2_1.5.pdf): -1.0 (Supporting) / -2.0 (Moderate) / <=-4.0 (Strong) points per unaffected (non-A-T) adult (>18y) carrying VUA with a P/LP variant in trans (confirmed trans -4.0; phase unknown -2.0; homozygous lab setting -2.0 / database setting -1.0, max -2.0). No qualifying observations -> 0 points -> not met.
Evidence considered
gnomad_v2 / gnomad_v4 / gnomad_canada - variant absent (AF=0); no unaffected carriers or homozygotes; no database-setting BP2 observations (VCEP footnote 4).
clinvar - single germline submission (Labcorp, Pathogenic, SCV002154400) with no unaffected-carrier or in-trans co-occurrence data; final classification not used as evidence per protocol.
PMID:10864201 / PMID:12105990 - the only germline observation is affected A-T proband AT35RM; no unaffected adult carrying the VUA with a P/LP variant in trans is described.
vcep_atm_pm3_bp2_1_5 - BP2 points table requires an unaffected (non-A-T) adult (>18y) with VUA in trans with a P/LP ATM variant; 0 qualifying observations -> 0 points -> not met.
Still missing
No unaffected (non-A-T) adult carrier observations with a co-occurring P/LP variant in trans were available from any source; meeting BP2 for this variant would require an unaffected-adult carrier cohort screen that is not present in this case.
PS3Not assessed: no direct functional assay evidence was available; the sole functional-screen entry is a computational prediction, which the VCEP excludes.
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Reasoning
No variant-specific functional assay evidence is available for NM_000051.4:c.5574G>A (p.Trp1858Ter), a nonsense variant. The governing ClinGen HBOP ATM VCEP v1.5 PS3 rules (cspec) require direct assay evidence that the variant fails to rescue an ATM-specific feature (PS3_Supporting) or fails to rescue both an ATM-specific feature and radiosensitivity (PS3_Moderate); the specification explicitly states 'Do not use as strong.' The VCEP-approved assays (Mitui 2009/PMID 18634022, Barone 2009/PMID 19431188, Scott 2002/PMID 11805335; vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1) confer calibrated strength ONLY when the variant under assessment is confirmed to have been tested in those specific papers, and the calibration table itself is not a per-variant results table. None of those three papers is present in this case's evidence bundle, so testing of p.Trp1858Ter in an approved assay could not be confirmed or excluded. The only variant-specific functional-screen entry (Sun et al. 2025, vcep_suppl_tables1_pmid_40580951, Table S1 row c.5574G>A) is classified 'Non-functional' but carries DeepATM_predicted=Yes and Confidence='Computational prediction', meaning it is a deep-learning model extrapolation rather than a direct functional measurement; per the VCEP index guidance such rows 'must not be presented as functional evidence'. Full-text checks of the ClinVar-cited papers available in the bundle (PMID:10864201, PMID:12105990, PMID:23807571, PMID:25614872) found no mention of c.5574G>A / p.Trp1858Ter. PS3 is therefore not assessed, and needs_human_review is flagged per VCEP guidance because the Sun et al. table is the only PS3/BS3-adjacent evidence for this variant.
Rule
ATM VCEP v1.5 (cspec): PS3 Strong - 'Do not use as strong.' PS3 Moderate - 'Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.' PS3 Supporting - 'Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency.'
Evidence considered
ClinGen HBOP ATM VCEP v1.5 PS3 rule (cspec): 'Do not use as strong'; PS3 Moderate 'Use when a variant fails to rescue both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity'; PS3 Supporting 'Use when a variant fails to rescue an ATM specifc feature, only (e.g. phosphorylation of ATM-specific targets). Do not use for radiosensitivity-only as that is not a feature specific to ATM deficiency'.
VCEP-approved assay calibration (vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1): ATM kinase-activity assays (Mitui 2009, Barone 2009, Scott 2002; stable transfection of ATM cDNA into ATM-null LCLs, Western blot of substrate phosphorylation after irradiation) approved with proposed PS3_Supporting; ATM radiosensitivity assay approved only for Mitui 2009 with proposed PS3_Moderate, but only combinable with a kinase-activity result. Table is calibration-only and does not report which variants were tested.
Sun et al. 2025 Table S1 (vcep_suppl_tables1_pmid_40580951), row hg38 11:108304752 G>A / c.5574G>A / p.W1858* (exon 37, Nonsense): Classification 'Non-functional', Confidence 'Computational prediction', DeepATM_predicted 'Yes' — not a direct functional measurement; excluded as PS3 evidence.
Full-text searches of PMID:10864201, PMID:12105990, PMID:23807571, PMID:25614872 for c.5574G>A / p.Trp1858Ter / W1858: zero matches; no variant-specific functional assay data retrievable from the case bundle.
Still missing
No VCEP-approved assay result for p.Trp1858Ter: the three approved papers (Mitui 2009/PMID 18634022, Barone 2009/PMID 19431188, Scott 2002/PMID 11805335) are not in the case bundle, so whether this variant was tested in a kinase-activity or radiosensitivity rescue assay is unknown and must be checked directly in those papers.
Sun et al. 2025 (PMID 40580951) Table S1 row for c.5574G>A is DeepATM_predicted=Yes / Confidence='Computational prediction' (Combined_score -2.757, Classification 'Non-functional'): model extrapolation only, explicitly excluded from functional evidence; no direct prime-editing measurement exists for this variant in that screen.
None of the retrieved full texts (PMID:10864201, PMID:12105990, PMID:23807571, PMID:25614872) mentions c.5574G>A / p.Trp1858Ter; no other variant-specific functional study was identified in the bundle.
PP1Not assessed: no segregation data exists; no affected relative, parental, or meiosis testing is reported for this variant.
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Reasoning
PP1 is applicable under the ATM VCEP v1.5 with autosomal-recessive strengths: Supporting = segregation in 1 affected relative, Moderate = 2 affected relatives, Strong = >=3 affected relatives (cspec doc 639508985). The only proband-level documentation of c.5574G>A is patient AT35RM, compound heterozygous with c.3576G>A (PMID 10864201 Table 1; PMID 12105990 Table 1/Fig. 2), studied via EBV-transformed lymphoblastoid cell lines; neither paper reports genotyping of any affected relative, parental testing, or meioses for this variant. The two AT cohort papers cited by the ClinVar submission were checked in full text and neither reports c.5574G>A at all: Huang et al. 2013 (PMID 23807571) collected parental samples in its 8-patient/6-family cohort but its 12 identified mutations do not include c.5574G>A, and Podralska et al. 2014 (PMID 25614872) lists the complete mutation set of 24 families in Table 2 without c.5574G>A. Because no segregation data (informative or otherwise) for this variant exists in the case evidence, PP1 cannot be applied at any strength; per instruction, insufficient evidence returns not_assessed with the gap identified rather than a met/not_met call.
Rule
PP1 (AR condition, ATM VCEP v1.5): Supporting = segregation in 1 affected relative; Moderate = segregation in 2 affected relatives; Strong = segregation in >=3 affected relatives
PMID 12105990 (Tsuchida 2002): AT35RM compound heterozygote with '3576 G->A' and '5574 G->A' (fragments b and c); proband-level observation only, no segregation data
PMID 23807571 (Huang 2013): parental samples collected in cohort, but c.5574G>A absent from the 12 reported mutations; no segregation data for this variant
PMID 25614872 (Podralska 2014): complete Table 2 mutation list for 24 families reviewed; c.5574G>A absent; carrier genotyping reported only for other variants
No segregation data in affected relatives: PP1 would require the variant to segregate with disease in >=1 affected relative (Supporting), 2 (Moderate) or >=3 (Strong) per the ATM VCEP v1.5; no affected-relative genotyping results for c.5574G>A are available in any source in the case evidence.
BS3Not assessed: no calibrated assay evidence that the variant preserves ATM function was available.
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Reasoning
No evidence that c.5574G>A (p.Trp1858Ter) preserves or rescues ATM function is available. The governing ClinGen HBOP ATM VCEP v1.5 BS3 rules (cspec) require direct assay evidence that the variant rescues both an ATM-specific feature and radiosensitivity (BS3_Moderate) or rescues either one (BS3_Supporting). The VCEP-approved assays (Mitui 2009/PMID 18634022, Barone 2009/PMID 19431188, Scott 2002/PMID 11805335; vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1) confer calibrated BS3_Supporting strength only when the variant under assessment is confirmed to have been tested in those papers; none of those papers is present in this case's evidence bundle. The only variant-specific functional-screen entry (Sun et al. 2025 Table S1, vcep_suppl_tables1_pmid_40580951, row c.5574G>A) is a DeepATM computational extrapolation (DeepATM_predicted=Yes, Confidence='Computational prediction'), which the VCEP index guidance excludes from functional evidence, and in any case it predicts 'Non-functional' rather than rescue. Retrieved full texts (PMID:10864201, PMID:12105990, PMID:23807571, PMID:25614872) do not mention the variant. BS3 is therefore not assessed; needs_human_review is flagged per VCEP guidance because no calibrated assay result exists for this variant.
Rule
ATM VCEP v1.5 (cspec): BS3 Moderate - 'Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.' BS3 Supporting - 'Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.'
Evidence considered
ClinGen HBOP ATM VCEP v1.5 BS3 rule (cspec): BS3 Moderate 'Use when a variant rescues both an ATM specifc feature (e.g. phosphorylation of ATM-specific targets) AND radiosensitivity.'; BS3 Supporting 'Use when a variant rescues EITHER an ATM specifc feature OR rescues radiosensitivity.'
VCEP-approved assay calibration (vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1): approved kinase-activity assays carry proposed BS3_Supporting; approved radiosensitivity assay (Mitui 2009 only) carries BS3_Supporting that can be added to the kinase BS3_Supporting. Calibration-only; requires confirmation the variant was tested in the cited papers.
Sun et al. 2025 Table S1 (vcep_suppl_tables1_pmid_40580951), row c.5574G>A / p.W1858*: Classification 'Non-functional', DeepATM_predicted 'Yes', Confidence 'Computational prediction' — not a direct functional measurement and not rescue evidence; excluded from BS3.
Full-text searches of PMID:10864201, PMID:12105990, PMID:23807571, PMID:25614872 for c.5574G>A / p.Trp1858Ter / W1858: zero matches; no variant-specific rescue data retrievable from the case bundle.
Still missing
No rescue/functional data from a VCEP-approved assay: the three approved papers (Mitui 2009/PMID 18634022, Barone 2009/PMID 19431188, Scott 2002/PMID 11805335) are not in the case bundle, so whether p.Trp1858Ter was tested for rescue of kinase activity or radiosensitivity is unknown.
Sun et al. 2025 (PMID 40580951) Table S1 row for c.5574G>A is DeepATM_predicted=Yes (computational extrapolation, 'Non-functional' classification) — no direct functional measurement; cannot support BS3.
No benign/likely-benign functional validation or other rescue evidence for this variant identified anywhere in the bundle.
Not applicable · 16· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: this is a nonsense change, and PS1 applies only to missense or splice-region variants.
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Reasoning
Governing framework is the ClinGen HBOP ATM VCEP v1.5 (CSpec 639508985), which takes precedence over generic ACMG/AMP. The VCEP PS1 specification has two sub-paths: (1) standard missense PS1 - same amino acid change as an established P/LP variant, used for missense changes as long as splicing is ruled out for both alterations; (2) the ATM PS1 Splicing table, for splice-region variants whose predicted splice event precisely matches that of a reference P/LP variant at the same position, with equal or higher prediction strength. The variant under assessment, NM_000051.4:c.5574G>A (p.Trp1858Ter), is a nonsense/stop-gain variant (confirmed by Mutalyzer normalization and VariantValidator; ClinVar VCV001380184 variant title), not a missense change, and SpliceAI predicts no significant splice impact (max delta = 0.01), so neither PS1 sub-path is applicable. In addition, no alternate-nucleotide variant producing the same amino acid change at this residue (e.g., c.5573G>A also giving p.Trp1858Ter) is documented anywhere in the case evidence bundle (ClinVar exact-match record is the sole record for this position; no c.5573G>A or residue-1858 alternate entries appear in prefetch, evidence, or the reviewed publications). PS1 therefore cannot be applied to this variant under the governing VCEP.
Rule
ATM VCEP v1.5 PS1: 'Use for missense changes as long as splicing is ruled-out for both alterations. Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect.' (standard sub-path inapplicable to a nonsense variant with no predicted splice impact)
Evidence considered
ATM VCEP v1.5 (CSpec 639508985) PS1 rule: standard path restricted to missense changes with splicing ruled out for both alterations; splicing-table path for splicing variants with similar predicted/observed splice defects.
ATM_PS1_1.5.pdf: PS1 guide covers missense and splice-region variants; splicing sub-path requires the VUA's predicted event to precisely match the reference variant's predicted event and equal-or-higher prediction strength.
SpliceAI lookup for NM_000051.4:c.5574G>A: max delta score 0.01 - no significant predicted splice impact.
No alternate-nucleotide variant at the same codon (c.5573G>A or other) present in prefetch.json, evidence.json, or the reviewed full texts (PMID 10864201, 12105990, 25614872).
Still missing
No established P/LP variant with the same amino acid change (p.Trp1858Ter via a different nucleotide change, e.g., c.5573G>A) is documented in the evidence bundle; if one is ever reported as P/LP, PS1 should be re-evaluated for this variant.
PS2VCEPNot applicable: the ATM VCEP does not apply de novo criteria, and no trio or parental testing data exists for this variant.
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Reasoning
Governing framework is the ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985, precedence_rank 1), which explicitly marks PS2 applicability as 'Not Applicable'; this VCEP does not apply de novo criteria for ATM-associated ataxia-telangiectasia (autosomal recessive). Independently, the case evidence bundle contains no de novo occurrence data for c.5574G>A: no proband/parent trio testing, no parental genotype results, and no paternity/maternity confirmation are reported in any source. The variant is documented only in the AT proband-derived cell line AT35RM (compound heterozygous with c.3576G>A; PMID 10864201, PMID 12105990), which carries no de novo information. PS2 therefore contributes no evidence.
VCEP rule
Applicability: Not Applicable per ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985)
Case evidence bundle (review_manifest, case_summary, evidence, literature_pass, prefetch, full-texts): no de novo or parental testing data for c.5574G>A
Still missing
No proband-parental trio data exists in the case evidence; applying PS2 would require documented de novo occurrence with confirmed parental identity, but the governing VCEP declares PS2 Not Applicable regardless.
PM1VCEPNot applicable: the ATM VCEP declares PM1 not applicable, and the variant is a stop-gain, not a missense substitution.
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Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 (CSpec 639508985) explicitly declares PM1 'Not Applicable' for ATM, so generic ACMG/AMP PM1 (missense in a functionally important domain/hotspot) is not applied. Independently, this variant is a nonsense/truncating change (p.Trp1858Ter), not a missense substitution, and the Cancer Hotspots query for ATM W1858 returned no statistically significant hotspot, so no domain/hotspot evidence for PM1 exists regardless of framework. The ATM VCEP domain note (ATM_PVS1_1.5.pdf, referencing PMID 28508083) treats the FAT, PI3-K, and FATC regions as one contiguous domain, but this does not create PM1 applicability for a stop-gain variant.
VCEP rule
PM1: Not Applicable per ATM VCEP v1.5 (CSpec 639508985)
Variant is a nonsense change p.Trp1858Ter, not a missense substitution (ClinVar VCV001380184 annotation).
Cancer Hotspots search for 'ATM W1858': no statistically significant hotspot (evidence.json hotspots result).
ATM_PVS1_1.5.pdf domain note: FAT/PI3-K/FATC considered one contiguous domain (PMID 28508083); informational only, does not activate PM1 for a stop-gain variant.
PM4N/ANot applicable: PM4 is for stop-loss variants; this is a stop-gain (nonsense) change.
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Reasoning
ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985) defines PM4 as: 'Use for stop-loss variants.' (default strength Pathogenic Moderate). The variant under assessment is a stop-gain (nonsense) change, NM_000051.4:c.5574G>A -> p.(Trp1858Ter), which creates a premature termination codon rather than extending/altering the protein C-terminus; it is therefore outside the scope of PM4 as specified by the VCEP. The null consequence of this variant is already captured by PVS1 (see above), and PM4 and PVS1 are mutually exclusive mechanisms for a stop-gain allele. PM4 is not applicable.
Rule
PM4 (Moderate): Use for stop-loss variants (ClinGen HBOP ATM VCEP v1.5); not applicable to stop-gain/nonsense variants
Evidence considered
ClinGen HBOP ATM VCEP v1.5 (cspec, doc 639508985) PM4 rule: 'Use for stop-loss variants.' - the variant is a stop-gain (p.Trp1858Ter), not a stop-loss, so PM4 does not apply
PM6VCEPNot applicable: the ATM VCEP marks PM6 not applicable, and no unconfirmed-de-novo or parental testing data exists.
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Reasoning
Governing framework is the ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985), which explicitly marks PM6 (assumed de novo without confirmation of parental identity) applicability as 'Not Applicable'. Independently, no de novo or parental testing data for c.5574G>A exists anywhere in the case evidence bundle (no trio data, no parental genotypes, no unconfirmed-de-novo observation). The only reported occurrence is in the AT proband-derived cell line AT35RM, compound heterozygous with c.3576G>A (PMID 10864201, PMID 12105990). PM6 therefore contributes no evidence.
VCEP rule
Applicability: Not Applicable per ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985)
Case evidence bundle (review_manifest, case_summary, evidence, literature_pass, prefetch, full-texts): no de novo or parental testing data for c.5574G>A
Still missing
No unconfirmed-de-novo observation for c.5574G>A is reported in any source; the governing VCEP declares PM6 Not Applicable regardless.
PP2VCEPNot applicable: the ATM VCEP declares PP2 not applicable, and the variant is a truncating change, not missense.
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Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 (CSpec 639508985) explicitly declares PP2 'Not Applicable' for ATM, so the generic ACMG/AMP PP2 (low rate of benign missense variation in a gene where missense is a common mechanism of disease) is not applied. The variant is additionally a nonsense/truncating change (p.Trp1858Ter), outside the missense scope of PP2.
VCEP rule
PP2: Not Applicable per ATM VCEP v1.5 (CSpec 639508985)
PP4VCEPNot applicable: the ATM VCEP routes phenotype evidence through the PM3/BP2 points system and marks PP4 not applicable.
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Reasoning
The ClinGen HBOP ATM VCEP v1.5 explicitly marks PP4 'Not Applicable' (cspec doc 639508985). The VCEP instead routes phenotype specificity through the PM3/BP2 points system, where an A-T clinical diagnosis is granted a 'confident' (or 'consistent') phenotype weight ('Phenotypes associated with A-T are very specific and do not generally require differential diagnosis'). PP4 is therefore not applied for this variant under the governing specification.
VCEP rule
Not Applicable per HBOP ATM VCEP v1.5 (cspec doc 639508985)
PP5VCEPNot applicable: the ClinVar record is a 1-star single-laboratory submission, not an expert-panel classification, so PP5 cannot be applied.
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Reasoning
Two independent grounds: (1) the ClinGen HBOP ATM VCEP v1.5 marks PP5 'Not Applicable'; (2) under the global PP5/BP6 policy, PP5 may be triggered only by an exact-variant ClinVar expert-panel classification (Pathogenic/Likely pathogenic). The ClinVar record for this exact variant (VCV001380184, variation 1380184) is 'Pathogenic' with review status 'criteria provided, single submitter' (1 star) from a single clinical laboratory (Labcorp Genetics/Invitae, SCV002154400); expert_panels is empty and expert_panel_submissions = 0. This is an ordinary laboratory submission, which must never trigger PP5. The literature-pass candidate PMID:20301317 (GeneReviews 'Hereditary Ataxia Overview') is a general review containing no exact-variant expert-panel classification and was dismissed.
VCEP rule
Not Applicable per HBOP ATM VCEP v1.5 (cspec doc 639508985); PP5/BP6 global policy additionally requires an exact-variant ClinVar expert-panel classification, which does not exist here
Evidence considered
ClinVar VCV001380184: classification Pathogenic, review status 'criteria provided, single submitter', 1 submission (SCV002154400, Labcorp Genetics/Invitae), 1 star, no expert panel submissions - not an expert-panel classification.
BS2VCEPNot applicable: the ATM VCEP explicitly marks BS2 not applicable for ATM.
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Reasoning
ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985) explicitly marks BS2 as Not Applicable for ATM. Under this governing specification no healthy-adult/homozygote population observation is adjudicated for BS2, so the criterion is not evaluated regardless of population data.
VCEP rule
BS2: Not Applicable per ClinGen HBOP ATM VCEP v1.5
BS4VCEPNot applicable: the ATM VCEP marks BS4 not applicable, and no family non-segregation data exists.
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Reasoning
Governing framework is the ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985), which explicitly marks BS4 (absence of segregation in affected family members) applicability as 'Not Applicable'. Independently, no non-segregation data exists for c.5574G>A in the case evidence bundle: no affected family member has been reported as not carrying the variant, and no family studies of this variant are reported in any source. BS4 therefore contributes no evidence.
VCEP rule
Applicability: Not Applicable per ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985)
BP1VCEPNot applicable: the ATM VCEP declares BP1 not applicable, and the variant is a truncating change, not missense.
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Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 (CSpec 639508985) explicitly declares BP1 'Not Applicable' for ATM, so the generic ACMG/AMP BP1 (missense variant in a gene where only truncating variants cause disease) is not applied. ATM is well established to harbor pathogenic missense variants, and the variant under assessment is itself a truncating change (p.Trp1858Ter), not a missense variant.
VCEP rule
BP1: Not Applicable per ATM VCEP v1.5 (CSpec 639508985)
BP3VCEPNot applicable: the ATM VCEP marks BP3 not applicable, and this is a nonsense substitution, not an in-frame repeat-region indel.
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Reasoning
ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985) explicitly declares BP3 as 'Not Applicable' for ATM, so no repeat-region in-frame-indel adjudication is performed under the governing specification. Independently, the generic ACMG/AMP BP3 (in-frame indels in a repeat region without known function) would not apply to this variant either: it is a single-nucleotide nonsense substitution (p.Trp1858Ter), not an in-frame indel, and no repeat-region context applies. BP3 is not applicable.
VCEP rule
BP3: Not Applicable per ClinGen HBOP ATM VCEP v1.5 (and variant is not an in-frame indel in a repeat region under generic ACMG/AMP)
BP4N/ANot applicable: per the lab override, the BP4 splicing sub-path (SpliceAI ≤0.1) is not applied to nonsense variants whose mechanism is protein truncation.
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Reasoning
BP4 is not applicable to this nonsense variant (p.(Trp1858Ter)): neither of the two VCEP BP4 sub-paths applies. (1) Missense sub-path (REVEL <=0.249) is inapplicable to a nonsense variant and REVEL is unavailable (NA in pipeline lookup and in Sun et al. 2025 Table S1). (2) Splicing sub-path (SpliceAI <=0.1) is restricted by the lab curator override recorded in vcep_materials gene_notes to non-missense variants for which splicing is the primary plausible mechanism (synonymous variants and intronic variants outside canonical +/-1,2 positions); a nonsense variant's primary mechanism is premature protein truncation, not splicing, so the splicing sub-path must not be used to clear it. EXPLICIT OVERRIDE STATEMENT (required by gene_notes): the lab override changes the outcome from what the ATM VCEP v1.5 literal text alone would produce - taken literally, 'Splicing: No predicted impact via splicing (SpliceAI <=0.1)' would have met BP4 for this variant (SpliceAI max delta 0.01 <=0.1). Under the override, BP4 is not applied, so no benign computational weight is assigned to a truncating variant whose damaging mechanism is protein-level rather than splice-level. Sun et al. 2025 Table S1 (DeepATM_predicted=Yes, 'Non-functional' by model extrapolation; REVEL/AlphaMissense/EVE all NA) provides no benign-leaning computational signal that maps to any VCEP BP4 threshold.
Rule
ATM VCEP v1.5 BP4: Missense REVEL <=0.249; Splicing: no predicted impact via splicing (SpliceAI <=0.1), with lab override restricting the splicing sub-path to non-missense variants for which splicing is the primary plausible mechanism.
Evidence considered
cspec: ClinGen HBOP ATM VCEP v1.5 BP4 rule (missense REVEL <=0.249; splicing SpliceAI <=0.1) and lab curator override in gene_notes restricting the splicing sub-path to non-missense variants where splicing is the primary plausible mechanism
spliceai: SpliceAI max delta score 0.01 - meets the literal numeric BP4 splicing threshold but excluded from application by the override for a nonsense variant
vcep_suppl_tables1_pmid_40580951: Table S1 row c.5574G>A - REVEL/AlphaMissense/EVE NA, DeepATM_predicted=Yes; no BP4-relevant benign computational signal
Still missing
No evidence gap affecting the outcome; BP4 exclusion for nonsense variants is a variant-type/mechanism determination under the lab override, not a missing-data issue.
If the lab override were not in force, the literal VCEP text would meet BP4 on SpliceAI <=0.1 alone; this policy decision is flagged in warnings for downstream review.
BP5VCEPNot applicable: the ATM VCEP marks BP5 not applicable, and no alternate molecular basis of disease is documented.
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Reasoning
The ClinGen HBOP ATM VCEP v1.5 explicitly marks BP5 'Not Applicable'. In addition, no evidence in the bundle indicates the variant was found in a case with an alternate molecular basis for disease, so BP5 would not be triggered even under generic ACMG/AMP.
VCEP rule
Not Applicable per HBOP ATM VCEP v1.5 (cspec doc 639508985)
BP6VCEPNot applicable: the ClinVar record is a 1-star single-laboratory Pathogenic submission, not a benign expert-panel classification, so BP6 cannot be applied.
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Reasoning
Two independent grounds: (1) the ClinGen HBOP ATM VCEP v1.5 marks BP6 'Not Applicable'; (2) under the global PP5/BP6 policy, BP6 may be triggered only by an exact-variant ClinVar expert-panel Benign/Likely benign classification. The ClinVar record for this exact variant (VCV001380184) is Pathogenic (1 star, single clinical laboratory, Labcorp Genetics/Invitae) - neither benign nor expert-panel - so BP6 cannot be triggered.
VCEP rule
Not Applicable per HBOP ATM VCEP v1.5 (cspec doc 639508985); BP6 global policy additionally requires an exact-variant ClinVar expert-panel Benign/Likely benign classification, which does not exist here
Evidence considered
ClinVar VCV001380184: classification Pathogenic (single laboratory, 1 star) - no expert-panel Benign/Likely benign classification exists for the exact variant.
BP7N/ANot applicable: BP7 applies to synonymous and deep intronic variants; this is an exonic nonsense change.
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Reasoning
BP7 is not applicable: the ATM VCEP v1.5 BP7 rule applies to synonymous variants and deep intronic variants (further than, but not including, +7 at donor sites and further than, but not including, -21 at acceptor sites). This variant is an exonic nonsense change (p.(Trp1858Ter)), which is neither synonymous nor intronic. The BP7_Strong(RNA)/BP7_Moderate(RNA) sub-paths require an observed lack of aberrant RNA for silent substitutions and intronic variants; the case bundle contains no RNA assay data for this variant, and those sub-paths are likewise scoped to silent/intronic variants, not nonsense. No BP7 is therefore assigned.
Rule
ATM VCEP v1.5 BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively; BP7(RNA) for observed lack of aberrant RNA in silent substitutions and intronic variants.
Evidence considered
cspec: ClinGen HBOP ATM VCEP v1.5 BP7 rule (synonymous and deep intronic variants >+7 donor / >-21 acceptor; BP7(RNA) for silent substitutions and intronic variants) - variant class (nonsense) falls outside the rule's scope
Still missing
No RNA-based assay result is available in the case bundle; irrelevant to the outcome because BP7/BP7(RNA) are scoped to synonymous and deep intronic variants and this variant is nonsense.
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…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in ATM—Select a row to find it on the plot; use the link to open its page.
Protein
Location
Classification
Link
gnomAD v4.1Allele count data not recorded
gnomAD v2.1Allele count data not recorded
gnomAD-Canada v1.0Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
SpliceAI acceptor lossat -16 bp
0.000
SpliceAI acceptor gainat +28 bp
0.010
SpliceAI donor lossat +471 bp
0.000
SpliceAI donor gainat +100 bp
0.000
Pangolin splice lossmagnitude shown
-0.040
Pangolin splice gain
0.040
Other predictors
REVEL
Not available
BayesDel
0.653
How the predictions were used
PP3Not met: SpliceAI max delta 0.01 is well below the 0.2 splicing threshold, and the missense sub-path does not apply to a nonsense variant.
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Reasoning
Variant is a nonsense change, NM_000051.4:c.5574G>A, p.(Trp1858Ter) (consequence_class=nonsense), so the VCEP PP3 missense sub-path (REVEL >0.7333) is not applicable, and the VCEP PP3 splicing sub-path (SpliceAI >=0.2 for silent, missense/in-frame and intronic variants outside donor/acceptor +/-1,2) does not enumerate nonsense variants. Evaluating the splice path anyway for completeness: SpliceAI max delta score = 0.01 (DS_AG 0.01; DS_AL/DS_DG/DS_DL 0.0), well below the 0.2 threshold -> no predicted splice impact, PP3 not met. REVEL is unavailable for this variant (pipeline lookup not found; Sun et al. 2025 Table S1 row for c.5574G>A also REVEL=NA), and the missense sub-path would not apply to a nonsense variant regardless. BayesDel score 0.652534 was retrieved but is treated as insufficiently calibrated (no verified published threshold nameable for this pipeline) and is in any case not part of the VCEP PP3 rule. Sun et al. 2025 Table S1 reports CADD phred 42 and boostDM 0.991 with DeepATM_predicted=Yes (Confidence='Computational prediction'), i.e. the 'Non-functional' classification is model extrapolation, not a functional measurement, and no VCEP-calibrated PP3 threshold exists for CADD/boostDM; therefore it confers no PP3. Secondary computational signals pointing to loss-of-function are consistent with the truncating mechanism already captured by PVS1 (another group) and are not double-counted here.
Rule
ATM VCEP v1.5 PP3: Missense REVEL >0.7333; Splicing: predicted impact via splicing (SpliceAI >=0.2) for silent, missense/in-frame and intronic variants outside donor and acceptor 1,2 sites.
Evidence considered
spliceai: SpliceAI max delta score 0.01 for NM_000051.4:c.5574G>A (11-108175479-G-A, GRCh37) - below ATM VCEP v1.5 PP3 splicing threshold of >=0.2
REVEL score not available for this variant (pipeline lookup and Sun et al. 2025 Table S1 both report NA); because the variant is nonsense the missense sub-path is inapplicable, so this gap does not change the outcome.
No VCEP-calibrated threshold exists for CADD/boostDM/AlphaMissense, so the Sun et al. 2025 computational scores cannot be mapped to a PP3 strength.
SpliceAI is the only splice predictor available; no RNA-based splice assay data for this variant is present in the case bundle (would belong to PVS1_RNA/BP7(RNA) review rather than PP3).
BP4N/ANot applicable: per the lab override, the BP4 splicing sub-path (SpliceAI ≤0.1) is not applied to nonsense variants whose mechanism is protein truncation.
Details ▾Hide ▴
Reasoning
BP4 is not applicable to this nonsense variant (p.(Trp1858Ter)): neither of the two VCEP BP4 sub-paths applies. (1) Missense sub-path (REVEL <=0.249) is inapplicable to a nonsense variant and REVEL is unavailable (NA in pipeline lookup and in Sun et al. 2025 Table S1). (2) Splicing sub-path (SpliceAI <=0.1) is restricted by the lab curator override recorded in vcep_materials gene_notes to non-missense variants for which splicing is the primary plausible mechanism (synonymous variants and intronic variants outside canonical +/-1,2 positions); a nonsense variant's primary mechanism is premature protein truncation, not splicing, so the splicing sub-path must not be used to clear it. EXPLICIT OVERRIDE STATEMENT (required by gene_notes): the lab override changes the outcome from what the ATM VCEP v1.5 literal text alone would produce - taken literally, 'Splicing: No predicted impact via splicing (SpliceAI <=0.1)' would have met BP4 for this variant (SpliceAI max delta 0.01 <=0.1). Under the override, BP4 is not applied, so no benign computational weight is assigned to a truncating variant whose damaging mechanism is protein-level rather than splice-level. Sun et al. 2025 Table S1 (DeepATM_predicted=Yes, 'Non-functional' by model extrapolation; REVEL/AlphaMissense/EVE all NA) provides no benign-leaning computational signal that maps to any VCEP BP4 threshold.
Rule
ATM VCEP v1.5 BP4: Missense REVEL <=0.249; Splicing: no predicted impact via splicing (SpliceAI <=0.1), with lab override restricting the splicing sub-path to non-missense variants for which splicing is the primary plausible mechanism.
Evidence considered
cspec: ClinGen HBOP ATM VCEP v1.5 BP4 rule (missense REVEL <=0.249; splicing SpliceAI <=0.1) and lab curator override in gene_notes restricting the splicing sub-path to non-missense variants where splicing is the primary plausible mechanism
spliceai: SpliceAI max delta score 0.01 - meets the literal numeric BP4 splicing threshold but excluded from application by the override for a nonsense variant
vcep_suppl_tables1_pmid_40580951: Table S1 row c.5574G>A - REVEL/AlphaMissense/EVE NA, DeepATM_predicted=Yes; no BP4-relevant benign computational signal
Still missing
No evidence gap affecting the outcome; BP4 exclusion for nonsense variants is a variant-type/mechanism determination under the lab override, not a missing-data issue.
If the lab override were not in force, the literal VCEP text would meet BP4 on SpliceAI <=0.1 alone; this policy decision is flagged in warnings for downstream review.
BP7N/ANot applicable: BP7 applies to synonymous and deep intronic variants; this is an exonic nonsense change.
Details ▾Hide ▴
Reasoning
BP7 is not applicable: the ATM VCEP v1.5 BP7 rule applies to synonymous variants and deep intronic variants (further than, but not including, +7 at donor sites and further than, but not including, -21 at acceptor sites). This variant is an exonic nonsense change (p.(Trp1858Ter)), which is neither synonymous nor intronic. The BP7_Strong(RNA)/BP7_Moderate(RNA) sub-paths require an observed lack of aberrant RNA for silent substitutions and intronic variants; the case bundle contains no RNA assay data for this variant, and those sub-paths are likewise scoped to silent/intronic variants, not nonsense. No BP7 is therefore assigned.
Rule
ATM VCEP v1.5 BP7: Use for synonymous and deep intronic variants defined as further than (but not including) +7 and further than (but not including) -21 at donor and acceptor sites, respectively; BP7(RNA) for observed lack of aberrant RNA in silent substitutions and intronic variants.
Evidence considered
cspec: ClinGen HBOP ATM VCEP v1.5 BP7 rule (synonymous and deep intronic variants >+7 donor / >-21 acceptor; BP7(RNA) for silent substitutions and intronic variants) - variant class (nonsense) falls outside the rule's scope
Still missing
No RNA-based assay result is available in the case bundle; irrelevant to the outcome because BP7/BP7(RNA) are scoped to synonymous and deep intronic variants and this variant is nonsense.
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.652534.
9 paper records listed. 2 cited in the classification.
Cited in the classification
ATM protein and p53-serine 15 phosphorylation in ataxia-telangiectasia (AT) patients and at heterozygotes.
Delia D et al. · 2000 Jun
Delia et al. characterize ATM protein expression and p53-Ser15 phosphorylation in cells from A-T patients and heterozygotes. The full text was searched for this variant and does not mention c.5574G>A, p.Trp1858Ter, or W1858, so no variant-specific protein-expression evidence for this allele is present.
→ PM3 · moderate→ PM5 · supportingNames this variant
Location Full text (publications/10864201.txt) searched for '5574', '1858', 'Trp1858', 'W1858' - no match found
Context Western blot analysis of ATM protein and radiation responses (G1 checkpoint, p53-Ser15 phosphorylation) in immortalized cells from AT patients and heterozygotes; cited in the ClinVar submission for this variant.
Detection of ATM gene mutation in human glioma cell line M059J by a rapid frameshift/stop codon assay in yeast.
Tsuchida R et al. · 2002 Aug
Tsuchida et al. describe a yeast-based frameshift/stop-codon assay for ATM mutations and apply it to the human glioma cell line M059J. The full text was searched for this variant and does not mention c.5574G>A, p.Trp1858Ter, or W1858, so no variant-specific functional data for this allele are present.
→ PM3 · moderate→ PM5 · supportingNames this variant
AT35RM has a G to A transition at position 3576 in one allele (3576 G→A) and a G to A transition at position 5574 (5574 G→A) in the other allele.
Location Full text (publications/12105990.txt) searched for '5574', '1858', 'Trp1858', 'W1858' - no match found
Context Yeast URA3 fusion frameshift/stop-codon functional assay for ATM truncating mutations; applied to M059J glioma cell line; cited in the ClinVar submission for this variant.
Other recorded publications
ATM Mutations in Cancer: Therapeutic Implications.
Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype.
Daniel et al. compare inactive Atm versus Atm loss on DSB repair in mouse cerebellum. The full text was searched for this variant and does not mention c.5574G>A, p.Trp1858Ter, or W1858; it provides general ATM-null biology only, with no variant-specific consequence evidence.
Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress.
Kang et al. study how loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress. The full text was searched for this variant and does not mention c.5574G>A, p.Trp1858Ter, or W1858; it provides general ATM-loss biology only, with no variant-specific consequence evidence.
Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.
Huang Y et al. · 2013
Huang et al. report twelve novel ATM mutations identified in Chinese ataxia-telangiectasia patients. The full text was searched for this variant and does not mention c.5574G>A, p.Trp1858Ter, or W1858, so this paper provides no variant-specific consequence evidence for the case under assessment.
Blood samples were collected from each A-T patients and their parents for mutation analysis, which includes the entire Atm gene coding sequence, adjacent intron regions and 3′UTR and 5′UTR
Full text (publications/23807571.txt) searched for '5574', '1858', 'Trp1858', 'W1858' - no match found
Ten new ATM alterations in Polish patients with ataxia-telangiectasia.
Podralska MJ et al. · 2014
Podralska et al. report ten new ATM alterations in Polish patients with ataxia-telangiectasia. The full text was searched for this variant and does not mention c.5574G>A, p.Trp1858Ter, or W1858, so this paper provides no variant-specific consequence evidence for the case under assessment.
As a result of molecular analysis, the status of recurrent mutation was confirmed and ten new ATM variants were detected.
Full text (publications/25614872.txt) searched for '5574', '1858', 'Trp1858', 'W1858' - no match found
Hereditary Ataxia Overview.
Adam MP et al. · 1993
GeneReviews 'Hereditary Ataxia Overview' - a general clinical review of hereditary ataxias. It was flagged by the literature triage as a candidate for PP5/PS4, but it is a background review with no exact-variant (c.5574G>A) content and no expert-panel classification of this variant. It cannot support PS4 (no case-control data) or PP5 (not an expert-panel classification), and was dismissed for this group.
This variant was interpreted by pipeline 7.1.0.
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