Classification rationale

PVS1PM2PM5 Pathogenic

ATM c.4231del

PVS1 (Very Strong): out-of-frame deletion creating premature stop p.(Ser1411AlafsTer40), predicted to trigger nonsense-mediated decay. PM2 (Supporting): absent from gnomAD v4.1 (AF=0), below the VCEP <=0.001% threshold. PM5 (Supporting): premature stop at residue ~1450, upstream of the p.Arg3047 truncation cutoff. Final: Pathogenic, via VCEP Rule4 — PVS1 very strong combined with PM2 and PM5 supporting.

PVS1 + PM2 + PM5 → Pathogenic

Gene diagram · NM_000051.4 · variants mapped to exon structure

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 3 applied · 10 assessed

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

Met at Very Strong: out-of-frame deletion creating premature stop p.(Ser1411AlafsTer40), predicted to trigger nonsense-mediated decay.

vcep_atm_pvs1_1_5: ClinGen HBOP ATM VCEP v1.5 PVS1 decision guide - defines null variants (incl. frameshift), LOF mechanism, constitutive exons, p.R3047 as most C-terminal pathogenic residue, FATKIN/HEAT domain notes for NMD-escaping variants.cspec: ATM VCEP v1.5 CSPEC ruleset - PVS1 default Very Strong, 'Use ATM PVS1 Decision Tree'.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.

cspec ↗pvs1_generic_framework ↗

✓

PM2 supporting Pathogenic

Met at Supporting: completely absent from gnomAD v4.1 (AF=0), below the VCEP <=0.001% frequency threshold.

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)

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗

✓

PM5 supporting Pathogenic

Met at Supporting: premature stop at residue ~1450, upstream of the p.Arg3047 truncation cutoff for pathogenic ATM variants.

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 rulepm5_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)

cspec ↗

Assessed · not applied

Pathogenic

PS3 Not assessed: insufficient evidence was available, as no VCEP-approved functional assay is documented to have tested c.4231del.

PS4 Not assessed: no case-control study of this exact variant was available, so no odds ratio or p-value could be computed.

PM3 Not assessed: no proband-level data (zygosity, phase, or phenotype) existed for c.4231del, so no PM3 points could be scored.

PP1 Not assessed: no family or segregation data for c.4231del were available.

PP3 Not met: SpliceAI max delta 0.01, far below the >=0.2 VCEP threshold.

Benign

BA1 Not met: absent from gnomAD v4.1 (AF=0), far below the >0.5% BA1 threshold.

BS1 Not met: absent from gnomAD v4.1 (AF=0), below the >0.05% BS1 threshold.

BS3 Not assessed: insufficient evidence was available, as no rescue or complementation assay data for c.4231del exist.

BP2 Not assessed: no unaffected-carrier observations with phase information for c.4231del were available.

BP4 Not met: a clean SpliceAI score (max delta 0.01) does not negate the variant's established frameshift truncation effect.

N/A · 15 PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP5 · BP6 · BP7

Research & evidence

Population frequency · supports pathogenic

gnomAD v4.1

gnomAD v2.1

v4.1

Absent from gnomAD v4.1.

v2.1

Absent from gnomAD v2.1.

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v2.1

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Pathogenic (1 clinical laboratory). (ClinVarID = 2106349)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01).

SpliceAI ↗

Functional Likely Oncogenic

OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.

OncoKB ↗

COSMIC

Cancer hotspots

Somatic evidence Not in COSMIC / hotspots

COSMIC

This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).

Hotspots

This variant does not lie in a statistically significant hotspot.

COSMIC ↗ Hotspots ↗

Literature · how each cited paper was used

2papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 7 further PMIDs triaged but not cited — see Sources & References.

Rule & framework references · cited for criterion definitions, not variant evidence

23807571 ↗ Twelve novel Atm mutations identified in Chinese ataxia telangiectasia patients.

25614872 ↗ Ten new ATM alterations in Polish patients with ataxia-telangiectasia.

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 7 PMIDs not cited in assessment

27413114 ↗ ATM Mutations in Cancer: Therapeutic Implications. ONCOKB

30348496 ↗ Inactive Atm abrogates DSB repair in mouse cerebellum more than does Atm loss, without causing a neurological phenotype. ONCOKB

30553448 ↗ Loss of ATM positively regulates Rac1 activity and cellular migration through oxidative stress. ONCOKB

20301317 ↗ Hereditary Ataxia Overview. CLINVAR

20301790 ↗ Ataxia-Telangiectasia. CLINVAR

24418350 ↗ EFNS/ENS Consensus on the diagnosis and management of chronic ataxias in adulthood. CLINVAR

20050888 ↗ EFNS guidelines on the molecular diagnosis of ataxias and spastic paraplegias. CLINVAR