ATM

Final classification

Pathogenic

ATM c.5574G>A · p.Trp1858Ter

ATM

PVS1 (Very Strong): stop-gain p.Trp1858Ter is a null allele predicted to trigger nonsense-mediated decay, removing the C-terminal kinase region.

Gene

ATM

Transcript

NM_000051.4

HGVS · transcript:coding

NM_000051.4:c.5574G>A

Consequence

N/A

GRCh38

chr11:108304752 G>A

GRCh37

chr11:108175479 G>A

Basis 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. ▾

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.

Classification rationale

PVS1PM2PM3PM5 Pathogenic

ATM c.5574G>A

PVS1 (Very Strong): stop-gain p.Trp1858Ter is a null allele predicted to trigger nonsense-mediated decay, removing the C-terminal kinase region. PM3 (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). PM2 (Supporting): absent from gnomAD v4.1, v2.1, and Canada (AF = 0), far below the ≤0.001% threshold. PM5 (Supporting): the premature stop at residue 1858 lies upstream of the VCEP truncation cutoff p.Arg3047. Overall: Pathogenic under the ClinGen HBOP ATM VCEP v1.5, from PVS1 (very strong) plus PM2 and PM5 (supporting) satisfying Rule 4 (≥1 very strong + ≥2 supporting), with PM3 (moderate) as additional support.

PVS1 + PM2 + PM3 + PM5 → Pathogenic

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

ATM NM_000051.4

Fetching transcript structure from UCSC…

Applied criteria · 4 applied · 8 assessed

Applied · 4

Strength Supporting Moderate Strong Very strong

✓

PVS1 very strong Pathogenic

Met (Very Strong): stop-gain at residue 1858 is a null allele predicted to trigger nonsense-mediated decay, removing the C-terminal kinase region.

ClinGen HBOP ATM VCEP v1.5 (cspec, doc 639508985) PVS1 rule: 'Use ATM PVS1 Decision Tree' with Very Strong as default strengthATM 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'

cspec ↗pvs1_generic_framework ↗

✓

PM2 supporting Pathogenic

Met (Supporting): absent from gnomAD v4.1, v2.1, and Canada (AF = 0), far below the ≤0.001% threshold.

gnomAD v4.1 variant lookup (gnomad_v4): chr11-108304752-G-A absent (AF = 0, no homozygotes)gnomAD v2.1 variant lookup (gnomad_v2): 11-108175479-G-A absentgnomAD-Canada v1.0 variant lookup (gnomad_canada): 11-108304752-G-A absent

gnomad_v4 ↗gnomad_v2 ↗gnomad_canada ↗cspec ↗

✓

PM3 moderate review Pathogenic

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).

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.vcep_atm_pm3_bp2_1_5 - ATM VCEP v1.5 PM3/BP2 table: confident phenotype + phase-unknown co-occurrence with P/LP variant = 2.0 points per unrelated A-T proband; PM3 Moderate = 2.0 points.

PMID:10864201 ↗PMID:12105990 ↗gnomad_v2 ↗gnomad_v4 ↗

✓

PM5 supporting Pathogenic

Met (Supporting): the premature stop at residue 1858 lies upstream of the VCEP truncation cutoff p.Arg3047.

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.

cspec ↗clinvar ↗PMID:12105990 ↗PMID:10864201 ↗

Assessed · not applied

Pathogenic

PS3 Not assessed: no direct functional assay evidence was available; the sole functional-screen entry is a computational prediction, which the VCEP excludes.

PS4 Not met: no case-control study of this variant exists; only case observations without a p-value or odds ratio are documented.

PP1 Not assessed: no segregation data exists; no affected relative, parental, or meiosis testing is reported for this variant.

PP3 Not 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.

Benign

BA1 Not met: allele frequency 0 (absent from gnomAD v4.1) is far below the >0.5% BA1 threshold.

BS1 Not met: allele frequency 0 (absent from gnomAD v4.1) is below the >0.05% BS1 threshold.

BS3 Not assessed: no calibrated assay evidence that the variant preserves ATM function was available.

BP2 Not met: no unaffected adult carrier of the variant with a second P/LP ATM allele is documented (0 BP2 points).

N/A · 16 PS1 · PS2 · PM1 · PM4 · PM6 · PP2 · PP4 · PP5 · BS2 · BS4 · BP1 · BP3 · BP4 · 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 = 1380184)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). BayesDel score = 0.652534.

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

6papers cited

Each card is an audit: what was searched, what was found, whether it names the variant, which criteria it fed, and why. 3 further PMIDs triaged but not cited — see Sources & References.

ATM protein and p53-serine 15 phosphorylation in ataxia-telangiectasia (AT) patients and at heterozygotes.

PMID 10864201 ↗ · Delia D et al. · 2000 Jun CLINVAR · case observation

Searched

c.5574G>Ap.Trp1858TerW1858*

Found

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.

Variant

✓ Names this variant — characterised directly

Applied to

→PVS1 very strong

→PM3 moderate

AT35RM: one unrelated A-T proband, confident phenotype, compound heterozygous c.3576G>A / c.5574G>A with phase unknown -> 2.0 points -> PM3 Moderate

→PM5 supporting

Patient AT35RM carrying the 5574 G→A allele has essentially absent ATM protein (<0.02), consistent with a null/truncating allele as assumed by the VCEP PM5 truncation-cutoff rule.

AT35RM 3576 GA / 5574 GA <0.02 0.83±0.16 (3)

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. · full text

Detection of ATM gene mutation in human glioma cell line M059J by a rapid frameshift/stop codon assay in yeast.

PMID 12105990 ↗ · Tsuchida R et al. · 2002 Aug CLINVAR · functional

Searched

c.5574G>Ap.Trp1858TerW1858*

Found

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.

Variant

✓ Names this variant — characterised directly

Applied to

→PVS1 very strong

→PM3 moderate

Consulted to confirm AT35RM is the same single proband counted from PMID:10864201 (avoids double counting); the M059J glioblastoma observation is somatic and contributes no germline PM3/BP2 evidence

→PM5 supporting

Functional corroboration that the 5574 G→A allele carries a premature stop codon (truncating), consistent with the truncation-cutoff PM5 rule application for p.Trp1858Ter.

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. · full text

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.

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

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

Sources & reference links

9Sources

CSpec VCEP

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots

Triaged references · 3 PMIDs not cited in assessment

27413114 ↗ ATM Mutations in Cancer: Therapeutic Implications. ONCOKB

20301317 ↗ Hereditary Ataxia Overview. CLINVAR

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