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.
ACMG/AMP criteria under ClinGen ATM VCEP v1.5, with the data and sources behind each one.
28 criteria with recorded statuses: 3 met · 4 not met · 6 not assessed · 15 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) applies; generic ACMG/AMP was not used for these criteria.
PVS1 met at Very Strong: c.4231del is a frameshift null variant, p.(Ser1411AlafsTer40), in ATM (LOF mechanism of disease); the PTC at codon 1450 (exon 29 of 63) is >55 nt upstream of the final exon-exon junction, so NMD is predicted; it is not at the extreme 3' end (upstream of p.Arg3047) and all exons are constitutive per the VCEP. Predicted truncation to 1450 of 3056 aa removes the C-terminal FATKIN critical domain.
PM4 not_applicable: ATM VCEP v1.5 limits PM4 to stop-loss variants; this is a frameshift/PTC null variant, not a stop-loss or in-frame length change.
BP3 not_applicable: ATM VCEP v1.5 marks BP3 Not Applicable; the variant is not an in-frame indel in a repetitive region.
No literature source in the case packet reports this specific variant; ClinVar-attributed PMIDs 23807571 and 25614872 were checked in full text and do not mention c.4231del, so no paper-based evidence was used for this group.
Governing framework: ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985, precedence rank 1) was found and used for all five criteria; no generic ACMG/AMP fallback was needed.
Variant class: NM_000051.4:c.4231del is a frameshift, NP_000042.3:p.(Ser1411AlafsTer40), in exon 28, with a premature termination codon at residue ~1450. All missense-centric criteria in this group are therefore structurally inapplicable or VCEP-declared not applicable.
PM1, PP2, BP1: the VCEP declares all three 'Not applicable' for ATM (PM1: benign and pathogenic variants co-occur in the same domains and hotspots are not well defined; PP2: no defined low rate of benign missense variation; BP1: pathogenic missense variants are known for ATM).
PS1: the VCEP restricts PS1 to missense changes (splicing ruled out for both alterations) and to splice-region variants via the ATM PS1 Splicing table. A frameshift cannot satisfy 'same amino acid change', and no splice-event path applies (SpliceAI max delta 0.01; no reference P/LP splice variant at this position). PS1 is not applicable.
PM5: met at Supporting strength under the VCEP truncation-cutoff rule — the variant is a frameshifting variant with a PTC (residue ~1450) upstream of p.Arg3047, the most C-terminal residue considered pathogenic for ATM. The VCEP explicitly prescribes PM5_Supporting (not moderate) for such variants and excludes only missense and start-loss variants. PM5_Supporting is a recognized combinable code in the VCEP ruleset (Rule19 supporting codes), so its use alongside PVS1 is permitted by the framework.
No same-residue (classic) PM5 comparator exists and none is required by the governing rule; the pipeline PM5 candidate collection (pm5_candidates.json) confirms zero same-residue candidates and the truncation-cutoff mode.
ClinVar's Pathogenic classification (Variation ID 2106349) was not used as evidence for any criterion in this group; it was used only to confirm variant identity.
Governing framework: ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985) applies; generic ACMG/AMP (PMID 25741868) not needed because the VCEP spec is complete and takes precedence.
PS2 and PM6: Not applicable per VCEP - ATM-associated ataxia-telangiectasia is autosomal recessive and de novo occurrences are not informative ('de novo AR conditions are unlikely to be informed by phase'). No de novo data exists in the case bundle regardless.
BS4: Not applicable per VCEP - informative lack-of-co-segregation instances in A-T families are too rare to weigh; such observations are handled via the BP2 pathway for biallelic unaffected individuals.
PP1: Applicable (AR condition) but not assessed - the case bundle contains no family segregation data (no affected relatives genotyped, no meioses), and neither ClinVar-cited paper (PMID 23807571, PMID 25614872) contains c.4231del in its full text, so no segregation evidence for this variant could be identified.
Net contribution of this group: no pathogenic (PS2/PM6/PP1) or benign (BS4) weight from segregation/de novo evidence.
The ClinVar Pathogenic classification (single submitter, 1 star) was treated as context only and was not used as evidence for any criterion in this group.
PS3 and BS3 are the only criteria in this group. The governing specification is the ClinGen HBOP ATM VCEP v1.5, which defines PS3/BS3 strictly in terms of complementation/rescue results in approved assays (ATM substrate phosphorylation in ATM-null LCLs: Mitui 2009, Barone 2009, Scott 2002; Mitui 2009 radiosensitivity combinable with a kinase result).
No variant-level functional evidence for c.4231del exists in this case bundle: the three VCEP-approved assay papers are not among the case sources, the only variant-level functional resource (Sun et al. 2025, PMID 40580951) is SNV-only and does not contain c.4231del, and the available full texts (PMID 23807571, PMID 25614872) do not mention the variant.
Both PS3 and BS3 are therefore not_assessed due to insufficient evidence; no strength is assigned. OncoKB's curated 'Likely Loss-of-function' annotation was considered and explicitly not used, as it is a curation label rather than a validated assay measurement.
This group's outcome does not change the overall variant classification; it simply records that functional assay evidence is unavailable.
Governing framework: ClinGen HBOP ATM VCEP v1.5 (framework_mode=vcep, precedence rank 1, CSPEC doc 639508985); generic ACMG is not used because an applicable gene-specific specification exists.
PS4: not assessed — the VCEP's quantitative case-control rule cannot be evaluated because no case-control study reporting c.4231del exists in the bundle; the only A-T cohort papers (PMID:23807571, PMID:25614872) do not contain the variant and lack control arms.
PP4, BP5: not applicable per explicit VCEP v1.5 applicability declarations; phenotype evidence is handled by the VCEP's PM3/BP2 points system.
PP5, BP6: not applicable — VCEP v1.5 declares them Not Applicable, and the ClinVar record (VCV002106349) has no expert-panel (3-star) classification of this exact variant (single 1-star laboratory submission only), so the expert-panel trigger is absent in both directions.
No final classification from any other source was used to infer any criterion in this group; the single-lab ClinVar Pathogenic assertion was treated solely as an indicator that no expert-panel classification exists.
Framework: ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985), the governing gene-specific specification for ATM; PM3 and BP2 are both marked Applicable and are scored with the VCEP points-based PM3/BP2 table (vcep_atm_pm3_bp2_1_5).
PM3: not_assessed. No A-T proband observation data for c.4231del exists in the case bundle (no zygosity, allele phase, second variant, or phenotype). The 1-star ClinVar Pathogenic record provides no allele-level detail and was not used to infer the criterion; its cited A-T cohort papers (PMID 23807571, PMID 25614872) were reviewed in full text and neither contains c.4231del. Zero points scoreable.
BP2: not_assessed. No unaffected (non-A-T) carrier observation of c.4231del in trans with a P/LP variant exists; gnomAD absence rules out population homozygous observations. Zero points scoreable.
This group contributes no points to the final classification; both criteria remain open pending proband/carrier-level allelic data.
Variant: NM_000051.4:c.4231del, NP_000042.3:p.(Ser1411AlafsTer40) - 1-bp frameshift deletion in ATM (exon 28). Governing framework: ClinGen HBOP ATM VCEP v1.5 (cspec, doc 639508985), supplemented by the local lab's BP4 missense/splicing policy override.
PP3 not_met: no computational evidence of deleterious effect. SpliceAI max delta 0.01 (< 0.2 threshold); the frameshift is outside the VCEP's enumerated PP3 splice sub-path types (silent, missense/in-frame, intronic) and the missense REVEL sub-path is inapplicable/unavailable; BayesDel unusable (non-SNV, no verified threshold); VCEP prohibits stacking PP3 on PVS1-type null variants. Sun et al. Table S1 (PMID 40580951) has no row for this deletion.
BP4 not_met: literal VCEP text would grant BP4 on SpliceAI <= 0.1 (0.01), but the lab's documented override restricts the splicing sub-path to variants for which splicing is the primary plausible mechanism (synonymous/intronic); a truncating frameshift is not such a variant, and the missense REVEL sub-path cannot apply to a non-SNV. Outcome differs from literal VCEP text solely due to the override, as required to be stated.
BP7 not_applicable: criterion is scoped to synonymous and deep intronic variants (plus RNA-based BP7 for silent/intronic variants); a frameshift deletion is outside this scope.
No double-counting: the single SpliceAI prediction (max delta 0.01) was evaluated for PP3 (below threshold) and BP4 (literal threshold met but overridden); it was not used for BP7, which is gated by variant class. It contributes no met criterion in this group.
No publication in the case packet (including ClinVar-cited PMID 23807571 and PMID 25614872) mentions c.4231del; no published in silico or RNA evidence for this exact variant was located.
Population-frequency adjudication used ClinGen HBOP ATM VCEP v1.5 (cspec, framework_mode=vcep) as the governing specification; generic ACMG/AMP was not applied because a gene-specific VCEP exists.
The variant (ATM c.4231del, p.Ser1411AlafsTer40) is absent from gnomAD v2.1, gnomAD v4.1 and gnomAD-Canada v1.0, so both VCEP population-frequency thresholds (BA1 grpmax AF >0.5%; BS1 grpmax AF >0.05%) are not met and the rarity threshold (PM2 <=0.001%) is met at Supporting strength.
BS2 is not applicable under the ATM VCEP v1.5 specification, so no strength was assigned.
Net population-group contribution: PM2 (Pathogenic Supporting) only; no benign population criteria apply.
Disease prevalence/penetrance reasoning (A-T is a rare recessive disorder) is already baked into the VCEP's calibrated AF thresholds and does not independently modify any criterion here.
No criteria match.
Met · 3
PVS1Very strongMet at Very Strong: out-of-frame deletion creating premature stop p.(Ser1411AlafsTer40), predicted to trigger nonsense-mediated decay.
Details ▾Hide ▴
Reasoning
Governing framework: ClinGen HBOP ATM VCEP v1.5 (cspec doc 639508985), PVS1 decision guide ATM_PVS1_1.5.pdf (adapted from the ClinGen SVI PVS1 decision tree, Abou Tayoun et al. 2018, PMID 30192042). Variant NM_000051.4:c.4231del normalizes to NP_000042.3:p.(Ser1411AlafsTer40), a single-nucleotide deletion causing an out-of-frame frameshift, i.e. a null variant (frameshift) explicitly covered by the VCEP PVS1 guide. (1) LOF is a known mechanism of disease for ATM (autosomal recessive ataxia-telangiectasia; the VCEP applies PVS1 to null variants in this gene). (2) NMD is predicted: the premature termination codon lies at codon 1450 (new-frame stop ~c.4352, in exon 29), more than 55 nt upstream of the final exon-exon junction of the 63-exon transcript, and the VCEP notes that all exons of the default transcript NM_000051.3/ENST00000278616.8 are constitutive with no major alternate splice isoforms that could rescue LOF. (3) Not subject to the extreme 3'-end caveat: the PTC at p.1450 is well upstream of p.Arg3047, the most C-terminal residue considered pathogenic per VCEP note 4. (4) Caveat 2 (in-frame exon skipping leaving the remainder of the protein intact) does not apply: this is a frameshift, and SpliceAI predicts no splice impact (max delta 0.01). The predicted truncation removes ~53% of the 3056-aa protein (last wild-type residue p.1410; 1450-aa mutant), including the entire C-terminal FAT/PI3K/FATC (FATKIN) region, which the VCEP treats as one contiguous critical domain (PMID 28508083); even in the hypothetical NMD-escape scenario the variant would still qualify for PVS1 per VCEP note 2. PVS1 therefore met at Very Strong per the decision tree.
Rule
ATM VCEP v1.5 PVS1 decision tree (adapted from PMID 30192042): null variant (frameshift) in a gene where LOF is a known mechanism, predicted to undergo NMD, not at the extreme 3' end -> PVS1 (Very Strong)
pvs1_generic_framework: ClinGen SVI PVS1 recommendations (Abou Tayoun et al. 2018, PMID 30192042; PMC6185798) - NMD criterion applied here: a PTC more than ~50-55 nt upstream of the final exon-exon junction is predicted to trigger NMD; this PTC (codon 1450, exon 29 of 63) satisfies that rule.
Still missing
No RNA-level or patient-cell confirmation of NMD for this specific variant (predicted NMD per decision-tree rules only).
The PVS1 decision-tree figure itself (page 3 of ATM_PVS1_1.5.pdf) is an image without a text layer; adjudication followed the guide's text (caveats, notes, p.R3047 boundary, FATKIN/HEAT notes) and the SVI decision-tree structure stated as its source (PMID 30192042).
PM2SupportingMet at Supporting: completely absent from gnomAD v4.1 (AF=0), below the VCEP <=0.001% frequency threshold.
Details ▾Hide ▴
Reasoning
ClinGen HBOP ATM VCEP v1.5 PM2 rule: frequency <=0.001% in the gnomAD v4 dataset; if n=1 in a single subpopulation, that is sufficiently rare and PM2_supporting applies. The variant is completely absent from gnomAD v4.1 (AF = 0, n = 0), which is at or below the <=0.001% threshold and even rarer than the n=1-in-one-subpopulation case explicitly deemed sufficient. Absence is independently corroborated by gnomAD v2.1 and gnomAD-Canada v1.0. PM2 is met at Supporting strength per the VCEP rule text. The query coordinates (chr11-108289094-CA-C / 11-108159821-CA-C) match the Mutalyzer-normalized allele (left-shift 3), so absence is not an artifact of coordinate or repeat-representation mismatch.
Rule
Frequency <=0.001% in gnomAD v4 dataset; if n=1 in a single sub population, that is sufficiently rare and PM2_supporting would apply.
Evidence considered
gnomAD v4.1 direct variant lookup for chr11-108289094-CA-C (dataset gnomad_r4) returned absent -> AF 0, satisfies VCEP frequency <=0.001%
gnomAD v2.1 direct variant lookup for 11-108159821-CA-C (dataset gnomad_r2_1) returned absent (corroborating rarity)
gnomAD-Canada v1.0 lookup for 11-108289094-CA-C returned absent (corroborating rarity)
Still missing
gnomAD v4.1 lookup captured presence/absence only (source_data empty); no AC/AN or per-subpopulation counts are available in the bundle to compute an exact grpmax AF, though absence makes AF = 0.
No independent check of other large population datasets (e.g., gnomAD v4 genomes, 1000 Genomes) beyond gnomAD v2.1, v4.1 and gnomAD-Canada v1.0.
PM5SupportingMet at Supporting: premature stop at residue ~1450, upstream of the p.Arg3047 truncation cutoff for pathogenic ATM variants.
Details ▾Hide ▴
Reasoning
The ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985) redefines PM5 as a truncation-cutoff rule, not classic same-residue missense PM5: 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047' at PM5_Supporting strength, with the instruction 'Use as PM5_Supporting (not moderate)' and 'Do not use for missense changes'. p.Arg3047 is the most C-terminal residue considered pathogenic for ATM per the VCEP ('The most 3'/C-Terminal residue considered to be pathogenic is p.R3047'). NM_000051.4:c.4231del is a frameshift (p.(Ser1411AlafsTer40)) with a premature termination codon at residue ~1450 (Mutalyzer predicted protein ends at position 1450, 40 residues into the shifted frame), which is well upstream (N-terminal) of p.Arg3047 (1450 < 3047). The variant is not a start-loss variant, and the rule's exclusion of missense changes does not apply. PM5 is therefore met at Supporting strength. No same-residue missense comparator exists (pipeline PM5 candidate collection found 0 same-residue candidates), but none is required by this rule. The VCEP combination ruleset explicitly lists PM5_Supporting among the supporting codes (Rule19), so the code is combinable with PVS1 as the framework intends.
Rule
ATM VCEP v1.5 PM5 (PM5_Supporting): Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047 (most C-terminal known pathogenic residue); not for missense or start-loss variants.
Evidence considered
cspec: ATM VCEP v1.5 PM5 entry — Supporting rule 'Apply to frameshifting or truncating variants with premature termination codons upstream of p.Arg3047'; instructions 'Use as PM5_Supporting (not moderate)', 'Do not use for missense changes'; PVS1 entry — 'The most 3'/C-Terminal residue considered to be pathogenic is p.R3047'
pvs1_variant_assessment: variant consequence scaffold — consequence_class 'frameshift', protein NP_000042.3:p.(S1411Afs*40), confirming the frameshift class used for the rule
pm5_candidates: pipeline candidate-collection artifact confirming PM5 mode 'truncation_cutoff_gene_specific' and zero same-residue (classic missense) comparator candidates; the PM5 call itself is grounded in the CSPEC rule text and variant consequence, not in this artifact's 'not_applicable' recommendation (which refers to classic same-residue missense PM5 search)
vcep_atm_pvs1_1_5: ATM VCEP v1.5 PVS1 guide domain/terminology notes consulted for the p.Arg3047 truncation boundary context
Still missing
NMD-proneness of the PTC (residue ~1450, exon 28 of 63) is inferred from position rather than confirmed by RNA studies; the VCEP's frameshift/truncating PM5 rule does not require RNA-level confirmation (the NMD requirement appears only in the separate splice-variant sub-rule), so this does not block application.
PP3Not met: SpliceAI max delta 0.01, far below the >=0.2 VCEP threshold.
Details ▾Hide ▴
Reasoning
Governing framework: ClinGen HBOP ATM VCEP v1.5 (cspec, doc 639508985). PP3 (Supporting) requires either missense REVEL > 0.7333 or splice-impact prediction SpliceAI >= 0.2 for silent, missense/in-frame, and intronic variants outside donor/acceptor +/-1,2 positions. The variant under assessment is NM_000051.4:c.4231del, a 1-bp frameshift deletion (NP_000042.3:p.(Ser1411AlafsTer40)) - not a missense, silent, in-frame, or intronic variant, so neither sub-path formally applies. Even under the VCEP's broader instruction that splice analysis be considered for all variant types, the available SpliceAI prediction is negative (max delta = 0.01; DS_DG = 0.01, all other deltas 0.0), far below the >= 0.2 threshold. REVEL was not retrievable (lookup skipped: 'not snv or no coords') and is inapplicable to a frameshift; BayesDel was also skipped (non-SNV) and in any case has no verified published threshold available to this pipeline. The VCEP's PP3 instructions additionally state 'PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes' - this frameshift is a PVS1-type null variant (assessed by the PVS1 group), so stacking PP3 on a splice prediction would be prohibited regardless. VCEP supporting spreadsheet Suppl_TableS1 (Sun et al. 2025, PMID 40580951) was checked for a pre-assigned PP3 code: it is an SNV-only table (29,375 rows) and contains no row for this deletion (the single row at genomic position 108289094 is a substitution at p.1409 per the table's own annotation, not this variant). No computational evidence of a deleterious effect is therefore available or applicable: PP3 not met.
Rule
ATM VCEP v1.5 PP3 (Supporting): 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 Lookup (spliceai): max delta score = 0.01 (DS_AG 0.0, DS_AL 0.0, DS_DG 0.01, DS_DL 0.0) for NM_000051.4:c.4231del - below the ATM VCEP v1.5 PP3 splice threshold of SpliceAI >= 0.2
ATM VCEP v1.5 (cspec): PP3 rule 'Missense: REVEL >.7333; Splicing: Predicted impact via splicing (SpliceAI >=0.2) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites'; instruction 'PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes'
Sun et al. 2025 Table S1 (vcep_suppl_tables1_pmid_40580951): checked for pre-assigned PP3 code; SNV-only table, c.4231del absent
Still missing
No REVEL score obtainable (1-bp deletion, not an SNV; lookup skipped by pipeline)
No BayesDel score (skipped as non-SNV; no verified published threshold exists for BayesDel regardless)
No RNA/splice assay data for this exact variant in the retrieved literature (PMID 23807571 and 25614872 do not mention c.4231del)
BA1Not met: absent from gnomAD v4.1 (AF=0), far below the >0.5% BA1 threshold.
Details ▾Hide ▴
Reasoning
ClinGen HBOP ATM VCEP v1.5 defines BA1 as grpmax filtering AF >0.5% in the gnomAD v4 dataset. Direct gnomAD v4.1 variant lookup for the normalized allele chr11-108289094-CA-C (dataset gnomad_r4) returned 'absent' (AF = 0), far below the 0.5% threshold. BA1 is therefore not met. The absence is corroborated by gnomAD v2.1 and gnomAD-Canada v1.0 lookups, which also returned absent.
Rule
Grpmax Filtering AF >0.5% in gnomAD v4 dataset
Evidence considered
gnomAD v4.1 direct variant lookup for chr11-108289094-CA-C (https://gnomad.broadinstitute.org/variant/chr11-108289094-CA-C?dataset=gnomad_r4) returned absent
gnomAD v2.1 direct variant lookup for 11-108159821-CA-C (dataset gnomad_r2_1) returned absent
gnomAD-Canada v1.0 lookup for 11-108289094-CA-C returned absent
Still missing
gnomAD v4.1 lookup captured presence/absence only (source_data empty); no per-subpopulation or grpmax AF breakdown is available in the bundle, though absence makes any grpmax AF = 0.
BS1Not met: absent from gnomAD v4.1 (AF=0), below the >0.05% BS1 threshold.
Details ▾Hide ▴
Reasoning
ClinGen HBOP ATM VCEP v1.5 defines BS1 as grpmax filtering AF >0.05% in the gnomAD v4 dataset. The variant is absent from gnomAD v4.1 (AF = 0), so the 0.05% threshold is not reached and BS1 is not met. Absence is corroborated by gnomAD v2.1 and gnomAD-Canada v1.0. No homozygotes or any carrier alleles were observed in any queried population dataset.
Rule
Grpmax Filtering AF >0.05% in gnomAD v4 dataset
Evidence considered
gnomAD v4.1 direct variant lookup for chr11-108289094-CA-C (dataset gnomad_r4) returned absent
gnomAD v2.1 direct variant lookup for 11-108159821-CA-C (dataset gnomad_r2_1) returned absent
gnomAD-Canada v1.0 lookup for 11-108289094-CA-C returned absent
Still missing
No per-subpopulation AF data captured in the bundle; absence across v2.1/v4.1/gnomAD-Canada is considered sufficient to rule out BS1.
BP4Not met: a clean SpliceAI score (max delta 0.01) does not negate the variant's established frameshift truncation effect.
Details ▾Hide ▴
Reasoning
CURATOR OVERRIDE CHANGES THE OUTCOME FROM THE VCEP'S LITERAL TEXT (stated explicitly as required by the BP4 missense/splicing policy override in the local gene framework, vcep_materials.json gene_notes). Literal ATM VCEP v1.5 text would grant BP4 from the splicing sub-path alone (SpliceAI <= 0.1; observed max delta = 0.01). The override restricts the BP4 splicing sub-path to non-missense variants for which splicing is the primary plausible mechanism (synonymous, intronic outside canonical +/-1,2); a frameshift deletion such as c.4231del (p.(Ser1411AlafsTer40)) is a null variant whose primary mechanism is protein truncation/loss of function - a clean SpliceAI score only rules out one possible damaging mechanism (splicing) and does not clear the variant's own established protein effect. The BP4 missense sub-path (REVEL <= 0.249) is inapplicable: the variant is not missense and REVEL was not retrievable (lookup skipped, 'not snv or no coords'). BayesDel is not usable (non-SNV skip; no verified published threshold). The VCEP's own instruction 'Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism' supports not crediting a clean splice score against a frameshift's protein-truncating effect. Sun et al. Table S1 (PMID 40580951) contains no row for this deletion (SNV-only), so no pre-assigned BP4 code exists. BP4 is therefore not applied: not_met.
Rule
ATM VCEP v1.5 BP4 (Supporting): Missense: REVEL score <= 0.249; Splicing: no predicted impact via splicing (SpliceAI <= 0.1) - as restricted by the local curator override to variants for which splicing is the primary plausible mechanism (synonymous, deep intronic); not applicable to frameshift null variants
Evidence considered
SpliceAI Lookup (spliceai): max delta score = 0.01 - would satisfy the literal VCEP BP4 splicing threshold (SpliceAI <= 0.1) but is not applied to this frameshift under the curator override (splicing is not the primary plausible mechanism for a truncating frameshift)
ATM VCEP v1.5 (cspec): BP4 rule 'Missense: REVEL score <=.249; Splicing: No predicted impact via splicing (SpliceAI <=0.1)'; instruction 'Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism'
Local lab override (vcep_materials.json gene_notes, BP4 missense/splicing policy): splicing sub-path restricted to non-missense variants for which splicing is the primary plausible mechanism (synonymous, intronic outside +/-1,2); frameshift variants excluded - outcome differs from literal VCEP text
Sun et al. 2025 Table S1 (vcep_suppl_tables1_pmid_40580951): checked for pre-assigned BP4 code; SNV-only table, c.4231del absent
Still missing
REVEL score unavailable (variant is a 1-bp deletion, not an SNV) - the missense BP4 sub-path cannot be evaluated
No RNA-based assay evidence (would be relevant to BP7(RNA), not to BP4) in retrieved literature; PMID 23807571 and 25614872 do not report this variant
PS3Not assessed: insufficient evidence was available, as no VCEP-approved functional assay is documented to have tested c.4231del.
Details ▾Hide ▴
Reasoning
Governing framework is the ClinGen HBOP ATM VCEP v1.5 (CSPEC found; framework_mode=vcep). VCEP PS3 rules: PS3_Supporting = variant fails to rescue an ATM-specific feature only (e.g., phosphorylation of ATM-specific targets); PS3_Moderate = fails to rescue BOTH an ATM-specific feature AND radiosensitivity; PS3 must NOT be used at strong ('Do not use as strong'). Approved assays (clingen_hbop_atm_supplementary_tables_1_and_2_v1.xlsx): stable transfection of ATM cDNA constructs into ATM-null LCLs with Western-blot readout of substrate phosphorylation (Mitui 2009/PMID 18634022, Barone 2009/PMID 19431188, Scott 2002/PMID 11805335) at PS3_Supporting, plus Mitui 2009 radiosensitivity (survival fraction) at PS3_Moderate only when combined with a kinase-activity result. This table is a methodology/calibration document, NOT a per-variant results table: PS3 may only be applied if c.4231del is confirmed to have been tested in one of those papers. No such confirmation is possible from this case bundle: none of the three approved assay papers is in the source registry or the publications folder, and no variant-level functional assay result for c.4231del appears anywhere in the bundle. The only variant-level functional resource present (Sun et al. 2025, PMID 40580951, Suppl Table S1) was inspected directly: it covers only SNVs (missense/synonymous/nonsense/splice/intronic) and contains no row for c.4231del (a single-nucleotide deletion), so it yields no functional measurement for this variant; it is also not one of the VCEP-approved assays. Full texts of the two ClinVar-cited patient-mutation papers (PMID 23807571, PMID 25614872) were searched for the variant (c.4231del / p.Ser1411AlafsTer40 / 1411): the variant is not mentioned, and neither paper reports any functional assay on it. OncoKB's curated 'Likely Loss-of-function' biological-effect annotation is a gene-context curation, not a validated assay measurement, and is not used as PS3 evidence. PS3 is therefore not_assessed: the VCEP defines an applicable rule and calibrated assay set, but no evidence exists that this variant was functionally tested.
Rule
ATM VCEP v1.5 PS3: PS3_Supporting = variant fails to rescue an ATM-specific feature only (e.g., phosphorylation of ATM-specific targets); PS3_Moderate = variant fails to rescue both an ATM-specific feature AND radiosensitivity; PS3_Strong: 'Do not use as strong.' Radiosensitivity-only failure gets no weight (not ATM-specific). Approved assays per clingen_hbop_atm_supplementary_tables_1_and_2_v1 (Mitui 2009, Barone 2009, Scott 2002) require the variant under assessment to be confirmed tested in the cited paper.
Evidence considered
cspec - ATM VCEP v1.5 PS3 rules: Supporting = fails to rescue an ATM-specific feature only; Moderate = fails to rescue both an ATM-specific feature and radiosensitivity; 'Do not use as strong.'
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 - VCEP-approved assay methodology and strength calibration (Mitui 2009/PMID 18634022, Barone 2009/PMID 19431188, Scott 2002/PMID 11805335 kinase assays; Mitui 2009 radiosensitivity combinable only with kinase result); explicitly not a per-variant results table
vcep_suppl_tables1_pmid_40580951 - Sun et al. 2025 Table S1 inspected: SNV-only rows (missense/synonymous/nonsense/splice/intronic); no c.4231del row (verified 0 exact hits), so no functional measurement for this variant
PMID:23807571 - Huang et al. 2013 Chinese A-T cohort full text searched: c.4231del/S1411 not among the 12 reported mutations; no functional assay on this variant
PMID:25614872 - Podralska et al. 2014 Polish A-T cohort full text searched: c.4231del/S1411 not reported; no functional assay on this variant
Still missing
No functional assay result for c.4231del in any VCEP-approved assay (Mitui 2009/PMID 18634022, Barone 2009/PMID 19431188, Scott 2002/PMID 11805335); these three papers are not in the source registry, so whether the variant was tested in them could not be checked.
No variant-level kinase-activity (ATM substrate phosphorylation) or radiosensitivity complementation data for this variant in any available source.
Sun et al. 2025 (PMID 40580951) saturation screen covers SNVs only and has no entry for c.4231del; even if it had, it is not a VCEP v1.5-approved assay and would require human review before use.
If functional adjudication is required, a curator must locate and check the three VCEP-approved assay papers for direct testing of c.4231del.
PS4Not assessed: no case-control study of this exact variant was available, so no odds ratio or p-value could be computed.
Details ▾Hide ▴
Reasoning
Governing framework is the ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985, precedence rank 1), which defines PS4 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 reporting this exact variant (NM_000051.4:c.4231del, p.Ser1411AlafsTer40) is present in the evidence bundle, so the required enrichment statistics (p-value, OR/HR/RR, CI) cannot be computed. The only candidate phenotype sources were the two A-T proband case series cited by the single ClinVar submission: PMID:23807571 (Huang et al., 12 novel ATM mutations in Chinese A-T patients) and PMID:25614872 (Podralska et al., 10 new ATM alterations in 24 Polish A-T patients). Neither reports c.4231del (the 23807571 full-text file is empty/0 lines; 25614872 lists c.1179_1180del, c.3802del, c.381del, c.6754del, c.7010_7011del, c.8441delC, c.8441delG and others but not c.4231del), and both are unselected case series without matched controls, so neither meets the VCEP's case-control threshold even in principle. The ClinVar Pathogenic label (VCV002106349, single laboratory, 1-star 'criteria provided, single submitter') is an ordinary laboratory assertion and was not used as PS4 evidence, per the rule never to infer a criterion from another source's final classification. Gap: a properly powered case-control study of this exact variant with p-value and OR/HR/RR (or lower 95% CI) would be needed to apply PS4 under the VCEP.
Rule
ATM VCEP v1.5 PS4: Case-control studies; p-value <=.05 AND (Odds ratio, hazard ratio, or relative risk >=2 OR lower 95% CI >=1.5).
Evidence considered
cspec: ATM VCEP v1.5 PS4 rule text defining the case-control threshold (p<=0.05 AND OR/HR/RR>=2 OR lower 95% CI >=1.5)
PMID:25614872: full text searched for c.4231del / p.Ser1411 — variant absent; cohort of 24 Polish A-T patients, 10 new ATM alterations, no case-control design
PMID:23807571: full text file empty (0 lines) — no retrievable content; cannot support variant-level enrichment
clinvar: single-lab 1-star Pathogenic submission not used as PS4 evidence (non-expert assertion)
Still missing
No case-control study (cases vs. matched controls) reporting the exact variant c.4231del with p-value and OR/HR/RR or lower 95% CI exists in the bundle; enrichment cannot be quantified
A-T cohort papers available (PMID:23807571, PMID:25614872) do not contain this variant and are case series without control arms or statistical enrichment analysis
PMID:23807571 full text is empty (0 lines) in publications/, so variant absence could not be independently verified in that paper
PM3Not assessed: no proband-level data (zygosity, phase, or phenotype) existed for c.4231del, so no PM3 points could be scored.
Details ▾Hide ▴
Reasoning
PM3 is Applicable under the governing ClinGen HBOP ATM VCEP v1.5 specification (CSPEC doc 639508985; ATM is autosomal recessive for ataxia-telangiectasia). The VCEP uses a points-based table: per unrelated A-T proband with confident phenotype, 4.0 points (confirmed in trans), 2.0 (phase unknown), 1.0 (second variant unidentified or VUS), 2.0 (homozygous, max 2 individuals); consistent phenotype scores half; PM3 strength thresholds are Supporting 1.0 / Moderate 2.0 / Strong 4.0 / Very Strong 8.0, and any co-occurring P/LP variant must itself be classified under VCEP specifications. The case bundle contains no proband-level data whatsoever for c.4231del: no zygosity, no allele phase, no second variant, and no A-T phenotype description for any carrier. The only clinical tie to A-T is the 1-star ClinVar record VCV002106349 (Pathogenic, single submitter SCV003322890, Labcorp), which reports no zygosity/phase/second-variant information, and per instruction its final classification was not used to infer this criterion. The two A-T cohort papers cited by that ClinVar submission (PMID 23807571, Chinese A-T cohort; PMID 25614872, Polish A-T cohort) were reviewed in full text: neither lists c.4231del among its reported mutations. gnomAD v2.1/v4.1/Canada show the variant absent, providing no population carrier or homozygous observations. With zero scoreable proband observations, PM3 cannot be assessed.
Rule
ATM VCEP v1.5 points-based PM3: sum points across unrelated A-T probands (confident phenotype 4.0 confirmed-trans / 2.0 phase-unknown / 1.0 second-variant-unidentified-or-VUS / 2.0 homozygous, max 2 individuals; consistent phenotype half). PM3_Supporting = 1.0 point, PM3 = 2.0 points, PM3_Strong = 4.0 points, PM3_VeryStrong >= 8.0 points. Co-occurring P/LP variant must be classified under VCEP specifications; variant must not exceed general population frequency >0.01%.
Evidence considered
ATM VCEP v1.5 PM3/BP2 points table (vcep_atm_pm3_bp2_1_5): PM3 points per unrelated A-T proband = 4.0 (confirmed in trans) / 2.0 (phase unknown) / 1.0 (second variant unidentified or VUS) / 2.0 (homozygous, max 2 individuals) for confident phenotype, half for consistent phenotype; PM3 thresholds Supporting 1.0 / Moderate 2.0 / Strong 4.0 / Very Strong 8.0; co-occurring P/LP variant must itself be classified under VCEP specifications; variant may not exceed general population frequency >0.01%
ClinVar VCV002106349 / SCV003322890 (Labcorp): Pathogenic, 1-star (criteria provided, single submitter, evaluated 2022-03-03), condition ataxia-telangiectasia; record contains no zygosity, allele-phase, or second-variant data; its Pathogenic label was not used to infer PM3
PMID:23807571 full text: 12 novel ATM mutations in 6 unrelated Chinese A-T families enumerated in discussion/Table 2 summary; c.4231del not among them (c.610G>T, c.1346G>C, c.1463G>A, c.1464G>A, c.2152_2154delinsAAAC, c.2413C>T, c.2680delG, c.3174G>A, c.3742_3743insGGAGGTTCT, c.6679C>T, c.6885G>T, c.7166C>G, c.8713_8714insCA)
PMID:25614872 full text, Table 2 (ATM mutations of 24 Polish A-T families): variants include c.8441delG, c.6095G>A, c.7630-2A>C, c.6145T>G, c.434T>G, c.6754_6754delA, c.5932G>T, c.1179_1180delGG, c.7010_7011delGT, c.381_381delA, c.3402+30_3402+32delATC, c.4007_4008insA, c.7606G>A, c.2250G>A; c.4231del not present
gnomAD v2.1, v4.1, and gnomAD-Canada: c.4231del absent from all datasets; no carrier or homozygous population observations
Still missing
No A-T proband observation data for c.4231del (zygosity, allele phase, second variant, phenotype classification) anywhere in the case bundle
ClinVar-cited A-T cohort papers (PMID 23807571, PMID 25614872) do not contain c.4231del in available full text, so no in-trans observation with a VCEP-classified P/LP variant can be scored
PMID 23807571 full text is only partially extracted (introduction/discussion with Table 2 summary); cannot exclude the variant in unextracted supplementary material, but it is not citable for this variant as-is
PP1Not assessed: no family or segregation data for c.4231del were available.
Details ▾Hide ▴
Reasoning
PP1 is applicable under ATM VCEP v1.5 (AR condition: segregation in 1 affected relative = PP1 Supporting; 2 affected relatives = PP1_Moderate; >=3 affected relatives = PP1_Strong; affected relatives must carry BOTH variants identified in the proband). However, no segregation evidence exists for c.4231del in this case: the case bundle contains no family/pedigree data, no genotyped affected relatives, and no reported meioses. The two papers cited by ClinVar submission SCV003322890 for this variant (PMID 23807571 Huang 2013; PMID 25614872 Podralska 2014) were both reviewed in full text and neither contains c.4231del/p.Ser1411 (Huang reports 12 other ATM mutations in 6 Chinese A-T families; Podralska reports 17 other ATM alterations in Polish A-T families), so neither can supply segregation data for this variant. PP1 is returned as not_assessed (not not_met) because the reason is complete absence of data rather than demonstrated non-segregation. Human review is flagged so that the ClinVar-citing laboratory's underlying evidence can be re-examined for any family segregation data on c.4231del.
Rule
ATM VCEP v1.5 AR Condition PP1: Segregation in 1 affected relative = PP1 (Supporting); 2 affected relatives = PP1_Moderate; >=3 affected relatives = PP1_Strong. Affected relatives must have both variants identified in proband. AD condition not used.
Evidence considered
ATM VCEP v1.5 (cspec) PP1: Applicable, AR condition rules (Supporting = 1 affected relative, Moderate = 2, Strong = >=3); 'Affected relatives must have both variants identified in proband'
ClinVar VCV002106349 (clinvar): Pathogenic, single submitter SCV003322890 (Labcorp), condition Ataxia-telangiectasia syndrome; cites PMIDs 23807571, 25614872, 28492532; record contains no segregation data
PMID:23807571 (Huang 2013) full text: 12 novel ATM mutations in 6 unrelated Chinese A-T families (Table 2); c.4231del/p.Ser1411 not present; no segregation data for the variant under assessment
PMID:25614872 (Podralska 2014) full text: 17 ATM alterations in Polish A-T families; c.4231del/p.Ser1411 not present; no segregation data for the variant under assessment
Still missing
No affected relatives genotyped for c.4231del; no segregation or meioses data in any case-bundle source
VCEP AR-condition PP1 requires affected relatives to carry BOTH proband variants - no family genotype data available
ClinVar-cited PMID 23807571 (Huang 2013) full text reviewed: c.4231del absent, no segregation data for this variant
ClinVar-cited PMID 25614872 (Podralska 2014) full text reviewed: c.4231del absent, no segregation data for this variant
BS3Not assessed: insufficient evidence was available, as no rescue or complementation assay data for c.4231del exist.
Details ▾Hide ▴
Reasoning
Governing framework is the ClinGen HBOP ATM VCEP v1.5. VCEP BS3 rules: BS3_Supporting = variant rescues EITHER an ATM-specific feature (e.g., phosphorylation of ATM-specific targets) OR radiosensitivity; BS3_Moderate = rescues BOTH an ATM-specific feature AND radiosensitivity. Approved assays are the same complementation assays as for PS3 (Mitui 2009/PMID 18634022, Barone 2009/PMID 19431188, Scott 2002/PMID 11805335; proposed BS3_Supporting), with Mitui 2009 radiosensitivity contributing BS3_Supporting only when combined with a kinase-activity result. Applying BS3 requires evidence that this exact variant restores ATM function in a validated assay; no rescue/complementation data for c.4231del exist anywhere in the case bundle. The three approved assay papers are not in the source registry or publications folder, so the variant's testing status in them cannot be confirmed. Sun et al. 2025 (PMID 40580951) was inspected directly and contains no row for c.4231del (SNV-only table). Full texts of PMID 23807571 and PMID 25614872 do not mention the variant and report no functional data for it. No source supports a benign functional effect, and none of the available content can be cited as BS3 evidence. BS3 is therefore not_assessed, with the gap being the complete absence of variant-level functional (rescue) data.
Rule
ATM VCEP v1.5 BS3: BS3_Supporting = variant rescues EITHER an ATM-specific feature OR radiosensitivity; BS3_Moderate = rescues BOTH an ATM-specific feature AND radiosensitivity. Approved assays per clingen_hbop_atm_supplementary_tables_1_and_2_v1 (Mitui 2009, Barone 2009, Scott 2002) require the variant under assessment to be confirmed tested in the cited paper.
Evidence considered
cspec - ATM VCEP v1.5 BS3 rules: Supporting = rescues EITHER an ATM-specific feature OR radiosensitivity; Moderate = rescues both an ATM-specific feature AND radiosensitivity
vcep_clingen_hbop_atm_supplementary_tables_1_and_2_v1 - approved assays propose BS3_Supporting for the three kinase-complementation assays; radiosensitivity BS3_Supporting only combinable with a kinase result; no per-variant data in the table itself
vcep_suppl_tables1_pmid_40580951 - inspected directly: no row for c.4231del (SNV-only), no rescue data for this variant
PMID:23807571 - full text searched: variant not reported; no functional data on this variant
PMID:25614872 - full text searched: variant not reported; no functional data on this variant
Still missing
No evidence that c.4231del rescues any ATM-specific feature or radiosensitivity in a validated assay; no variant-level functional data at all in the case bundle.
The three VCEP-approved assay papers (PMID 18634022, PMID 19431188, PMID 11805335) are not in the source registry, so direct testing of c.4231del in them could not be verified.
Sun et al. 2025 (PMID 40580951) does not cover deletions (SNV-only) and is not a VCEP-approved assay in any case.
If benign functional evidence is sought, a curator must check the approved assay papers for rescue testing of c.4231del.
BP2Not assessed: no unaffected-carrier observations with phase information for c.4231del were available.
Details ▾Hide ▴
Reasoning
BP2 is Applicable under the governing ClinGen HBOP ATM VCEP v1.5 specification. The VCEP assigns negative points per unaffected (non-A-T) individual carrying the variant with a P/LP variant in trans: -4.0 (confirmed trans), -2.0 (phase unknown), -2.0 (homozygous, laboratory setting) or -1.0 (homozygous, database setting, max -2.0); the individual should be >=18 years old with no evidence of A-T; BP2 strength thresholds are Supporting -1.0 / Moderate -2.0 / Strong <= -4.0. No unaffected-carrier observation with phase information exists in the case bundle: the ClinVar record contains no carrier or phase data, the ClinVar-cited A-T cohort papers (PMID 23807571, PMID 25614872) do not contain c.4231del, and the variant is absent from gnomAD v2.1/v4.1/Canada (no homozygous carriers). With zero scoreable observations, BP2 cannot be assessed.
Rule
ATM VCEP v1.5 points-based BP2: sum negative points across unaffected (non-A-T) individuals carrying the variant with a P/LP variant (confirmed trans -4.0 / phase unknown -2.0 / homozygous -2.0 lab or -1.0 database, max -2.0; individual >=18 years with no evidence of A-T). BP2 = -1.0 point, BP2_Moderate = -2.0 points, BP2_Strong <= -4.0 points.
Evidence considered
ATM VCEP v1.5 PM3/BP2 points table (vcep_atm_pm3_bp2_1_5): BP2 points per unaffected (non-A-T) individual with P/LP variant in trans = -4.0 (confirmed trans) / -2.0 (phase unknown) / -2.0 laboratory or -1.0 database setting (homozygous, max -2.0); BP2 thresholds Supporting -1.0 / Moderate -2.0 / Strong <= -4.0; individual must be >=18 years with no evidence of A-T
ClinVar VCV002106349 / SCV003322890 (Labcorp): Pathogenic, 1-star; no unaffected-carrier, zygosity, or phase data in record
PMID:23807571 and PMID:25614872 full texts: A-T cohort mutation lists do not contain c.4231del, so no carrier observations in trans are derivable
gnomAD v2.1, v4.1, and gnomAD-Canada: variant absent; no homozygous carrier observations
Still missing
No unaffected (non-A-T) individual observation of c.4231del in trans with a VCEP-classified P/LP ATM variant (confirmed phase or phase unknown)
No homozygous carrier observations in population or clinical data (gnomAD v2.1/v4.1/Canada absent; ClinVar record has no carrier-level detail)
No age/A-T-exclusion status available for any carrier of c.4231del, as required by the VCEP BP2 instructions (>=18 years, no evidence of A-T)
Not applicable · 15· recorded as not applicableShow reasons ▾Hide reasons ▴PS1N/ANot applicable: PS1 applies only to missense or splice-region variants; c.4231del is a frameshift.
Details ▾Hide ▴
Reasoning
Variant NM_000051.4:c.4231del is a 1-bp deletion producing a frameshift, NP_000042.3:p.(Ser1411AlafsTer40), not a missense or splice-region variant. The governing ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985) restricts PS1 to two paths: (1) missense changes 'as long as splicing is ruled-out for both alterations' (same amino acid change as an established P/LP variant), and (2) splice-region variants via the ATM PS1 Splicing table, which requires the variant-under-assessment's predicted splice event to precisely match a reference P/LP variant's predicted event. A frameshift with a premature termination codon cannot produce the 'same amino acid change' as any missense, so the missense path cannot apply; the splicing path cannot apply because c.4231del is an exonic frameshift with no predicted splice impact (SpliceAI max delta score 0.01, below the VCEP PP3 splicing threshold of >=0.2), and no reference P/LP splice variant at this position is present in the case evidence. PS1 is therefore not applicable to this variant class.
Rule
ATM VCEP v1.5 PS1: missense PS1 for same amino acid change (splicing ruled out for both alterations); ATM PS1 Splicing table for splicing variants. Not applicable to frameshift variants.
Evidence considered
cspec: ATM VCEP v1.5 PS1 entry — 'Use as ascribed for missense changes as long as a splice defect is ruled out for both variants; Use ATM PS1 Splicing table for splicing variants with similar predictions or observations of splice defect' (scope excludes frameshift variants)
vcep_atm_ps1_1_5: ATM VCEP v1.5 PS1 guide — prerequisite that the predicted event of the variant under assessment precisely match the predicted event of the reference P/LP variant (splicing path)
Still missing
PS1 would only become assessable if this variant were a missense substitution at p.Ser1411 with an established P/LP comparator at the same residue; no such comparator exists for this frameshift variant.
PS2VCEPNot applicable: ataxia-telangiectasia is autosomal recessive, so de novo occurrences are not informative under the ATM VCEP.
Details ▾Hide ▴
Reasoning
ATM VCEP v1.5 (ClinGen HBOP, cspec doc 639508985) marks PS2 'Not applicable' with the instruction: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.' Ataxia-telangiectasia (the associated condition in this case, per ClinVar) is autosomal recessive, so a de novo occurrence is not informative under this specification. Independently of the applicability ruling, the case bundle contains no proband or parental testing data at all: no de novo occurrence of c.4231del (confirmed or assumed) is documented in any source. No PS2 evidence exists either way.
VCEP rule
ATM VCEP v1.5: PS2 Not applicable - do not use for AD or AR disease; de novo occurrences not yet observed for this gene and de novo AR conditions are unlikely to be informed by phase
Evidence considered
ATM VCEP v1.5 (cspec) PS2 applicability = 'Not applicable'; instructionsToUse: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase'
Case bundle (review_manifest, case_summary, evidence.json, literature_pass.json): no proband or parental testing data for c.4231del
Still missing
No proband/parental genotype data in any case-bundle source; de novo occurrence of c.4231del never documented
VCEP applicability ruling alone excludes PS2 for this AR condition regardless of any future de novo observation
PM1VCEPNot applicable: the ATM VCEP disallows PM1 because germline mutational hotspots are not well defined for this gene.
Details ▾Hide ▴
Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985) declares PM1 'Not applicable' for ATM with the instruction 'Do not use: Benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time'. Additionally, PM1 is a missense/hotspot-domain criterion and this variant is a frameshift (p.(Ser1411AlafsTer40), exon 28), so no hotspot or functional-domain position assessment is performed for it. The VCEP's PVS1 guide notes the FAT/PI3-K/FATC regions are treated as one contiguous critical domain, but the VCEP still does not use PM1 as evidence for ATM.
VCEP rule
ATM VCEP v1.5 PM1: declared Not applicable (no defined germline mutational hotspots; benign and pathogenic variants co-occur in the same domains).
Evidence considered
cspec: ATM VCEP v1.5 PM1 entry — applicability 'Not applicable', instruction 'Do not use: Benign and pathogenic variants are known to occur within the same domains and germline mutational hotspots are not well defined at this time'
vcep_atm_pvs1_1_5: ATM VCEP v1.5 PVS1 guide domain notes (FAT/PI3-K/FATC contiguous domain, PMID 28508083) consulted for the domain question; does not change the VCEP's not-applicable determination for PM1
Still missing
No domain/hotspot localization assessment is performed because the VCEP declares PM1 not applicable for ATM; the VCEP's stated reason is that benign and pathogenic variants co-occur in the same domains and germline mutational hotspots are not well defined.
PM4N/ANot applicable: PM4 is restricted to stop-loss variants; c.4231del is an out-of-frame frameshift with a premature stop.
Details ▾Hide ▴
Reasoning
The governing ATM VCEP v1.5 specification restricts PM4 to stop-loss variants ('Use for stop-loss variants.'). c.4231del is an out-of-frame single-nucleotide deletion producing a frameshift with a premature termination codon, p.(Ser1411AlafsTer40) - not a stop-loss variant and not an in-frame protein-length change (in-frame indel). The variant's consequence is a truncating/null event handled under PVS1, so PM4 is not applicable under the VCEP specification.
Rule
ATM VCEP v1.5 PM4: use for stop-loss variants only
Evidence considered
cspec: ATM VCEP v1.5 PM4 rule - 'Use for stop-loss variants.' (Pathogenic Moderate); frameshift variants are outside this rule.
PM6VCEPNot applicable: ataxia-telangiectasia is autosomal recessive, so assumed de novo occurrences are not informative under the ATM VCEP.
Details ▾Hide ▴
Reasoning
ATM VCEP v1.5 (ClinGen HBOP, cspec doc 639508985) marks PM6 'Not applicable' with the instruction: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase.' Ataxia-telangiectasia is autosomal recessive, so an assumed de novo occurrence (without parental confirmation) is not informative under this specification. Independently, no de novo data (confirmed or assumed) for c.4231del exists in the case bundle. No PM6 evidence exists either way.
VCEP rule
ATM VCEP v1.5: PM6 Not applicable - do not use for AD or AR disease; de novo occurrences not yet observed for this gene and de novo AR conditions are unlikely to be informed by phase
Evidence considered
ATM VCEP v1.5 (cspec) PM6 applicability = 'Not applicable'; instructionsToUse: 'Do not use for AD or AR disease: Informative de novo occurrences have not yet been observed and de novo AR conditions are unlikely to be informed by phase'
Case bundle (review_manifest, case_summary, evidence.json, literature_pass.json): no proband or parental testing data for c.4231del
Still missing
No proband/parental genotype data in any case-bundle source; assumed de novo occurrence of c.4231del never documented
VCEP applicability ruling alone excludes PM6 for this AR condition regardless of any future de novo observation
PP2VCEPNot applicable: the ATM VCEP disallows PP2, as ATM lacks a defined low rate of benign missense variation.
Details ▾Hide ▴
Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985) declares PP2 'Not applicable' for ATM with the instruction 'Do not use: ATM does not have a defined low rate of missense benign variation'. Independent of the variant class, the gene-level premise of PP2 (low rate of benign missense variation with missense as a common disease mechanism) is not met for ATM under the VCEP. This variant is additionally a frameshift, not a missense, so PP2 cannot apply.
VCEP rule
ATM VCEP v1.5 PP2: declared Not applicable (ATM lacks a defined low rate of benign missense variation).
Evidence considered
cspec: ATM VCEP v1.5 PP2 entry — applicability 'Not applicable', instruction 'Do not use: ATM does not have a defined low rate of missense benign variation'
Still missing
No gene-level missense constraint ratio assessment is performed because the VCEP declares PP2 not applicable for ATM (no defined low rate of benign missense variation).
PP4VCEPNot applicable: the ATM VCEP routes phenotype evidence through its PM3/BP2 points system instead of PP4.
Details ▾Hide ▴
Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985) explicitly lists PP4 as 'Not Applicable'. The specification instead routes A-T phenotype information through its own PM3/BP2 points system (ATM_PM3_BP2_1.5.pdf), which grades proband phenotype as 'confident' vs 'consistent' A-T diagnosis and assigns points per unrelated proband. Because an applicable gene-specific specification exists and it declares PP4 non-applicable, generic ACMG PP4 (phenotype or family history highly specific for a genetic etiology) is not used for this variant.
VCEP rule
ATM VCEP v1.5: PP4 applicability = Not Applicable.
PP5VCEPNot applicable: no ClinVar expert-panel (3-star) classification of this variant exists to trigger PP5.
Details ▾Hide ▴
Reasoning
PP5 is declared 'Not Applicable' by the governing ATM VCEP v1.5 (CSPEC doc 639508985). Independently, the global PP5 trigger for this pipeline requires an exact-variant ClinVar expert-panel (3-star) classification of Pathogenic/Likely pathogenic. ClinVar VCV002106349 (variation 2106349) has zero expert-panel submissions (expert_panels: {}); its only submission is SCV003322890 from Labcorp Genetics (formerly Invitae), review status 'criteria provided, single submitter' (1 star, reviewed 2022-03-03). Per the governing rules, ordinary laboratory submissions, aggregate ClinVar labels, and non-expert assertions must never trigger PP5 — so even under generic ACMG the criterion cannot be applied. Result: not applicable under both the VCEP and the expert-panel trigger rule.
BS2VCEPNot applicable: the ATM VCEP explicitly marks BS2 not applicable; unaffected-carrier data is handled by its PM3/BP2 system.
Details ▾Hide ▴
Reasoning
The ClinGen HBOP ATM VCEP v1.5 specification explicitly marks BS2 as 'Not Applicable' (cspec applicability field). The governing VCEP supersedes generic ACMG/AMP for this gene, so generic BS2 (observed in trans with a pathogenic variant in a healthy adult) is not applied. Note: the VCEP's PM3/BP2 points system is the designated mechanism for handling observations in unaffected carriers, not BS2.
BS4VCEPNot applicable: the ATM VCEP disallows BS4 for autosomal recessive conditions like ataxia-telangiectasia.
Details ▾Hide ▴
Reasoning
ATM VCEP v1.5 (ClinGen HBOP, cspec doc 639508985) marks BS4 'Not applicable'. Instructions: 'AD Condition: Co-segregation analysis in low penetrance genes can lead to false positive results (PMID 32773770). AR Condition: Informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.' No lack-of-segregation observation (affected family member without the variant) for c.4231del exists in the case bundle either. No BS4 evidence exists either way.
VCEP rule
ATM VCEP v1.5: BS4 Not applicable - informative lack-of-co-segregation instances in A-T families too rare to weigh at this time (see BP2 pathway for biallelic unaffected individuals)
Evidence considered
ATM VCEP v1.5 (cspec) BS4 applicability = 'Not applicable'; instructionsToUse: 'AD Condition: Co-segregation analysis in low penetrance genes can lead to false positive results (PMID 32773770). AR Condition: Informative instances of lack of co-segregation in A-T families are too rare to be considered for weight at this time and can also be considered for BP2 if biallelic unaffected patients are observed in an A-T family.'
Case bundle (review_manifest, case_summary, evidence.json, literature_pass.json): no family genotype data for c.4231del
Still missing
No affected-family-member genotype data in any case-bundle source; non-segregation of c.4231del never observed
VCEP applicability ruling excludes BS4; any biallelic-unaffected observation would route to the BP2 pathway instead
BP1VCEPNot applicable: the ATM VCEP disallows BP1, as pathogenic missense variants are known in this gene.
Details ▾Hide ▴
Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985) declares BP1 'Not applicable' for ATM with the instruction 'Do not use: Missense pathogenic variants are known for ATM'. The premise of BP1 (a gene where primarily truncating variants cause disease) is false for ATM, which has established pathogenic missense variants. This variant is also a frameshift, not a missense, so the criterion cannot apply on either basis.
VCEP rule
ATM VCEP v1.5 BP1: declared Not applicable (pathogenic missense variants are known for ATM).
Evidence considered
cspec: ATM VCEP v1.5 BP1 entry — applicability 'Not applicable', instruction 'Do not use: Missense pathogenic variants are known for ATM'
Still missing
No truncating-vs-missense mechanism ratio assessment is performed because the VCEP declares BP1 not applicable for ATM (pathogenic missense variants are known for ATM).
BP3VCEPNot applicable: BP3 covers in-frame indels in repetitive regions; c.4231del is an out-of-frame deletion.
Details ▾Hide ▴
Reasoning
The governing ATM VCEP v1.5 specification explicitly declares BP3 'Not Applicable' for ATM. Independently, the generic BP3 definition (in-frame deletions/insertions in a repetitive region without known function) does not apply: c.4231del is an out-of-frame 1-bp deletion (frameshift) with a premature termination codon, not an in-frame indel in a repeat region.
VCEP rule
ATM VCEP v1.5: BP3 Not Applicable
Evidence considered
cspec: ATM VCEP v1.5 lists BP3 as 'Not Applicable'.
BP5VCEPNot applicable: the ATM VCEP explicitly lists BP5 as not applicable.
Details ▾Hide ▴
Reasoning
The governing ClinGen HBOP ATM VCEP v1.5 (CSPEC doc 639508985) explicitly lists BP5 as 'Not Applicable'. No evidence of an alternate molecular basis (e.g., a distinct pathogenic variant in another gene fully explaining the phenotype) is present anywhere in the evidence bundle, but the criterion is not used because the applicable gene-specific specification declares it non-applicable.
VCEP rule
ATM VCEP v1.5: BP5 applicability = Not Applicable.
BP6VCEPNot applicable: no ClinVar expert-panel (3-star) benign classification of this variant exists to trigger BP6.
Details ▾Hide ▴
Reasoning
BP6 is declared 'Not Applicable' by the governing ATM VCEP v1.5 (CSPEC doc 639508985). Independently, the global BP6 trigger for this pipeline requires an exact-variant ClinVar expert-panel (3-star) classification of Benign/Likely benign. ClinVar VCV002106349 contains no expert-panel submissions (expert_panels: {}); the sole submission (SCV003322890, Labcorp) is a 1-star 'criteria provided, single submitter' Pathogenic assertion. There is no expert-panel benign classification to trigger BP6, and the single-lab Pathogenic assertion is directionally opposite and non-expert. Result: not applicable under both the VCEP and the expert-panel trigger rule.
BP7N/ANot applicable: BP7 is limited to synonymous and deep intronic variants; c.4231del is a coding frameshift deletion.
Details ▾Hide ▴
Reasoning
ATM VCEP v1.5 BP7 (Supporting) is defined for synonymous and deep intronic variants (deep intronic defined as beyond but not including +7 at donor and beyond but not including -21 at acceptor sites), and BP7_Moderate/BP7_Strong(RNA) for an observed lack of aberrant RNA defect in silent substitutions and intronic variants. The variant under assessment, NM_000051.4:c.4231del (p.(Ser1411AlafsTer40)), is a coding frameshift deletion in exon 28 - it is neither synonymous nor intronic, and no RNA assay data exist for it in the retrieved literature. BP7 is therefore outside the criterion's scope for this variant type: not_applicable. SpliceAI was not used to drive BP7 because the criterion's applicability is gated by variant class, not by splice score; no double-counting of the SpliceAI prediction across PP3/BP4/BP7 was performed (SpliceAI was applied only to the PP3 and BP4 evaluations above).
Rule
ATM VCEP v1.5 BP7 (Supporting): use for synonymous and deep intronic variants beyond (but not including) +7 (donor) and -21 (acceptor); BP7_Moderate/Strong(RNA) for observed lack of aberrant RNA defect in silent substitutions and intronic variants
Evidence considered
ATM VCEP v1.5 (cspec): BP7 rule '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 defect for silent substitutions and intronic variants - variant is a frameshift deletion, outside scope
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
—
Transcript span
—
Strand
—
Variants mapped
—
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 -117 bp
0.000
SpliceAI acceptor gainat +481 bp
0.000
SpliceAI donor lossat +9 bp
0.000
SpliceAI donor gainat -28 bp
0.010
Pangolin splice lossmagnitude shown
-0.070
Pangolin splice gain
0.020
Other predictors
REVEL
Not available
BayesDel
Not available
How the predictions were used
PP3Not met: SpliceAI max delta 0.01, far below the >=0.2 VCEP threshold.
Details ▾Hide ▴
Reasoning
Governing framework: ClinGen HBOP ATM VCEP v1.5 (cspec, doc 639508985). PP3 (Supporting) requires either missense REVEL > 0.7333 or splice-impact prediction SpliceAI >= 0.2 for silent, missense/in-frame, and intronic variants outside donor/acceptor +/-1,2 positions. The variant under assessment is NM_000051.4:c.4231del, a 1-bp frameshift deletion (NP_000042.3:p.(Ser1411AlafsTer40)) - not a missense, silent, in-frame, or intronic variant, so neither sub-path formally applies. Even under the VCEP's broader instruction that splice analysis be considered for all variant types, the available SpliceAI prediction is negative (max delta = 0.01; DS_DG = 0.01, all other deltas 0.0), far below the >= 0.2 threshold. REVEL was not retrievable (lookup skipped: 'not snv or no coords') and is inapplicable to a frameshift; BayesDel was also skipped (non-SNV) and in any case has no verified published threshold available to this pipeline. The VCEP's PP3 instructions additionally state 'PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes' - this frameshift is a PVS1-type null variant (assessed by the PVS1 group), so stacking PP3 on a splice prediction would be prohibited regardless. VCEP supporting spreadsheet Suppl_TableS1 (Sun et al. 2025, PMID 40580951) was checked for a pre-assigned PP3 code: it is an SNV-only table (29,375 rows) and contains no row for this deletion (the single row at genomic position 108289094 is a substitution at p.1409 per the table's own annotation, not this variant). No computational evidence of a deleterious effect is therefore available or applicable: PP3 not met.
Rule
ATM VCEP v1.5 PP3 (Supporting): 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 Lookup (spliceai): max delta score = 0.01 (DS_AG 0.0, DS_AL 0.0, DS_DG 0.01, DS_DL 0.0) for NM_000051.4:c.4231del - below the ATM VCEP v1.5 PP3 splice threshold of SpliceAI >= 0.2
ATM VCEP v1.5 (cspec): PP3 rule 'Missense: REVEL >.7333; Splicing: Predicted impact via splicing (SpliceAI >=0.2) for silent, missense/in-frame and for intronic variants outside of donor and acceptor 1,2 sites'; instruction 'PP3 for splice predictions may not be applied in addition to PVS1 or PVS1_Variable(RNA) codes'
Sun et al. 2025 Table S1 (vcep_suppl_tables1_pmid_40580951): checked for pre-assigned PP3 code; SNV-only table, c.4231del absent
Still missing
No REVEL score obtainable (1-bp deletion, not an SNV; lookup skipped by pipeline)
No BayesDel score (skipped as non-SNV; no verified published threshold exists for BayesDel regardless)
No RNA/splice assay data for this exact variant in the retrieved literature (PMID 23807571 and 25614872 do not mention c.4231del)
BP4Not met: a clean SpliceAI score (max delta 0.01) does not negate the variant's established frameshift truncation effect.
Details ▾Hide ▴
Reasoning
CURATOR OVERRIDE CHANGES THE OUTCOME FROM THE VCEP'S LITERAL TEXT (stated explicitly as required by the BP4 missense/splicing policy override in the local gene framework, vcep_materials.json gene_notes). Literal ATM VCEP v1.5 text would grant BP4 from the splicing sub-path alone (SpliceAI <= 0.1; observed max delta = 0.01). The override restricts the BP4 splicing sub-path to non-missense variants for which splicing is the primary plausible mechanism (synonymous, intronic outside canonical +/-1,2); a frameshift deletion such as c.4231del (p.(Ser1411AlafsTer40)) is a null variant whose primary mechanism is protein truncation/loss of function - a clean SpliceAI score only rules out one possible damaging mechanism (splicing) and does not clear the variant's own established protein effect. The BP4 missense sub-path (REVEL <= 0.249) is inapplicable: the variant is not missense and REVEL was not retrievable (lookup skipped, 'not snv or no coords'). BayesDel is not usable (non-SNV skip; no verified published threshold). The VCEP's own instruction 'Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism' supports not crediting a clean splice score against a frameshift's protein-truncating effect. Sun et al. Table S1 (PMID 40580951) contains no row for this deletion (SNV-only), so no pre-assigned BP4 code exists. BP4 is therefore not applied: not_met.
Rule
ATM VCEP v1.5 BP4 (Supporting): Missense: REVEL score <= 0.249; Splicing: no predicted impact via splicing (SpliceAI <= 0.1) - as restricted by the local curator override to variants for which splicing is the primary plausible mechanism (synonymous, deep intronic); not applicable to frameshift null variants
Evidence considered
SpliceAI Lookup (spliceai): max delta score = 0.01 - would satisfy the literal VCEP BP4 splicing threshold (SpliceAI <= 0.1) but is not applied to this frameshift under the curator override (splicing is not the primary plausible mechanism for a truncating frameshift)
ATM VCEP v1.5 (cspec): BP4 rule 'Missense: REVEL score <=.249; Splicing: No predicted impact via splicing (SpliceAI <=0.1)'; instruction 'Use caution in applying the wrong type of computational evidence (protein vs. RNA) towards the cumulative body of evidence for the opposite mechanism'
Local lab override (vcep_materials.json gene_notes, BP4 missense/splicing policy): splicing sub-path restricted to non-missense variants for which splicing is the primary plausible mechanism (synonymous, intronic outside +/-1,2); frameshift variants excluded - outcome differs from literal VCEP text
Sun et al. 2025 Table S1 (vcep_suppl_tables1_pmid_40580951): checked for pre-assigned BP4 code; SNV-only table, c.4231del absent
Still missing
REVEL score unavailable (variant is a 1-bp deletion, not an SNV) - the missense BP4 sub-path cannot be evaluated
No RNA-based assay evidence (would be relevant to BP7(RNA), not to BP4) in retrieved literature; PMID 23807571 and 25614872 do not report this variant
BP7N/ANot applicable: BP7 is limited to synonymous and deep intronic variants; c.4231del is a coding frameshift deletion.
Details ▾Hide ▴
Reasoning
ATM VCEP v1.5 BP7 (Supporting) is defined for synonymous and deep intronic variants (deep intronic defined as beyond but not including +7 at donor and beyond but not including -21 at acceptor sites), and BP7_Moderate/BP7_Strong(RNA) for an observed lack of aberrant RNA defect in silent substitutions and intronic variants. The variant under assessment, NM_000051.4:c.4231del (p.(Ser1411AlafsTer40)), is a coding frameshift deletion in exon 28 - it is neither synonymous nor intronic, and no RNA assay data exist for it in the retrieved literature. BP7 is therefore outside the criterion's scope for this variant type: not_applicable. SpliceAI was not used to drive BP7 because the criterion's applicability is gated by variant class, not by splice score; no double-counting of the SpliceAI prediction across PP3/BP4/BP7 was performed (SpliceAI was applied only to the PP3 and BP4 evaluations above).
Rule
ATM VCEP v1.5 BP7 (Supporting): use for synonymous and deep intronic variants beyond (but not including) +7 (donor) and -21 (acceptor); BP7_Moderate/Strong(RNA) for observed lack of aberrant RNA defect in silent substitutions and intronic variants
Evidence considered
ATM VCEP v1.5 (cspec): BP7 rule '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 defect for silent substitutions and intronic variants - variant is a frameshift deletion, outside scope
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).
9 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
ATM Mutations in Cancer: Therapeutic Implications.
Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.
Huang Y et al. · 2013
Twelve novel ATM mutations in 8 Chinese A-T patients from 6 unrelated families are catalogued (Table 2: 4 nonsense, 5 frameshift, 1 splicing, 1 missense, 1 large genomic deletion). None of the listed variants is c.4231del/p.(Ser1411AlafsTer40); the variant under assessment is not reported in this paper, so it cannot support consequence-based evidence (PVS1/PM4/BP3).
The genetic analysis of Atm gene identified 12 disease-causing mutations in 6 unrelated A-T families (Table 2). The mutation types are diverse, including 4 nonsense (33.3 %), 1 splicing (8.3 %), 5 frameshift (42 %), 1 large genomic deletion (8.3 %), and 1 missense mutation (8.3). All the Atm mutations were novel.
Results section; Table 2 'Atm Mutations of eight patients from six families'
Ten new ATM alterations in Polish patients with ataxia-telangiectasia.
Podralska MJ et al. · 2014
Ten new ATM alterations plus recurrent mutations in 24 Polish A-T patients are reported (Table 2, e.g. AT01 c.8441delG p.Glu2814LysfsTer43; c.6095G>A exon 43 skipping; c.5932G>T; c.3402+30_3402+32delATC). None of the listed variants is c.4231del/p.(Ser1411AlafsTer40); the variant under assessment is not reported in this paper, so it cannot support consequence-based evidence (PVS1/PM4/BP3).
This variant was interpreted by pipeline 7.1.0.
The current version is 11.0.07.
Re-running queues a fresh interpretation; the result replaces this page when complete.
Re-runs are not free. Blank draws on today's public interpretation allowance; with a code, it uses one of that code's uses.