# NM_000051.4(ATM):c.2674A>T (p.Lys892Ter)

https://sugi.bio/variant/atm-p-lys892ter

## Summary

**ATM p.Lys892Ter (c.2674A>T)** is classified **Likely pathogenic** in ATM (ClinVar, Single submitter, 1 submitter). Absent from gnomAD v4.1; Associated with ataxia telangiectasia.

**At a glance:** Likely pathogenic · review: Single submitter · 1 submitter · 1 linked condition · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the ATM gene that is considered likely disease-causing, submitted by 1 submitter, and is linked to ataxia telangiectasia.

*Reference information, not medical advice, and not a prediction for any individual. A genetic counselor or clinician can interpret what it means for you and your family.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal recessive |
| Age of onset (of this condition) | Childhood, Infancy |
| Prevalence | 1-5 / 10 000 (Norway) |
| Clinical trials | 35 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | ATM is a diagnostic-grade gene on 27 Genomics England panels |

**Commonly reported features of Ataxia-telangiectasia** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Polycystic ovaries — Very frequent (99-80%)
- Strabismus — Very frequent (99-80%)
- Abnormality of eye movement — Very frequent (99-80%)
- Nystagmus — Very frequent (99-80%)
- Delayed puberty — Very frequent (99-80%)
- Ataxia — Very frequent (99-80%)
- Gait disturbance — Very frequent (99-80%)
- Tremor — Very frequent (99-80%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0005862/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [ATM](https://sugi.bio/atlas/gene/ATM/) |
| Protein change (HGVS p.) | p.Lys892Ter |
| Coding change (HGVS c.) | c.2674A>T |
| MANE Select transcript | [NM_000051](https://www.ncbi.nlm.nih.gov/nuccore/NM_000051) |
| Variant type | single nucleotide variant |
| Location | chr11:108268445-108268445 (GRCh38) |
| ClinVar | [VCV3393422](https://www.ncbi.nlm.nih.gov/clinvar/variation/3393422/) |

**All HGVS expressions:** `LRG_135:g.50614A>T`, `LRG_135t1:c.2674A>T`, `NC_000011.10:g.108268445A>T`, `NC_000011.9:g.108139172A>T`, `NG_009830.1:g.50614A>T`, `NM_000051.4:c.2674A>T`, `NM_001351834.2:c.2674A>T`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **Missense predictors (AlphaMissense/REVEL/SaProt) do not apply** to this variant type — they score amino-acid substitutions only. For non-missense variants the computational signal comes from conservation (below), not from a missing predictor score.
- Conservation: phyloP 11.097, GERP 2.68, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **nonsense (stop-gain)** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 18 of 63**, so the transcript is predicted to undergo NMD.
- CADD: **PHRED 37.0**. No single ClinGen-calibrated threshold exists and the expert panels that use CADD disagree — GUCY2D/AIPL1 require ≥ 20.0 for an untranslated-region variant, ABCA4 ≥ 28.1 for a synonymous or indel variant, the Pulmonary Hypertension panel imports Pejaver 2022's missense-calibrated numbers, and the Antibody Deficiencies panel declines CADD entirely for PIK3CD. CADD v1.7 also incorporates Zoonomia phyloP, so it partly re-expresses the conservation above. *Descriptive; no threshold applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for ATM (3,768 scored positions, the nearest 1 base away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Pangolin: Δ**0.29** (loss), gain 0.01 / loss 0.29. SpliceAI below 0.2. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*Computational predictors are not independent (ClinGen Variant Classification guidance): AlphaMissense (Cheng et al. 2023) carries the ACMG weight for missense and conservation (phyloP/GERP/phastCons) for non-missense; REVEL (Pejaver-2022 calibrated strength bands) and SaProt (Su et al. 2023, structure-aware, ClinVar-independent protein language model, raw LLR) are shown as orthogonal agreement signals, not additive. For frequency, the gnomAD v4.1 grpmax filtering allele frequency (FAF95) is ClinGen's designated BA1/BS1 input (gnomAD v4 guidance v3.0, June 2025); BA1/BS1 thresholds are disease-specific, not a blanket 5%. Predictions, not a clinical determination.*

## Gene constraint & dosage {#gene-context}

**ATM** population constraint: LOEUF 0.847, pLI 1.4847e-69, missense-Z 2.5412; ClinGen dosage — haploinsufficiency 3/3, triplosensitivity 0/3. *Lower LOEUF and higher pLI indicate a gene that tolerates loss-of-function poorly; ClinGen dosage is the curated haploinsufficiency call.*

Curated gene–disease validity (ClinGen):

- **ataxia telangiectasia** — Definitive (AR)
- **ATM-related cancer predisposition** — Definitive (AD)

## Protein context {#protein}

Residue **892** lies in a UniProt-annotated variant site (in at); an α-helix; a UniProt-annotated variant site (in at; uncertain significance).

**14 experimental structure(s)** (PDB): [5NP0](https://www.rcsb.org/structure/5NP0), [5NP1](https://www.rcsb.org/structure/5NP1), [6HKA](https://www.rcsb.org/structure/6HKA), [6K9K](https://www.rcsb.org/structure/6K9K), [6K9L](https://www.rcsb.org/structure/6K9L), [7NI4](https://www.rcsb.org/structure/7NI4).

## What this gene does {#gene-function}

*Describes the biological roles of ATM (the gene this variant disrupts) — not effects measured for this specific variant. A damaging variant is expected to affect these functions and pathways; the degree depends on the variant.*

**How this variant is thought to act:** ATM's established molecular role includes protein serine/threonine kinase activity. In Reactome, ATM is annotated in disease pathway(s) including **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function**, **Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function**.

**Disease mechanism (Reactome):** ATM loss or alteration is curated in [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331), [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646), [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192).

### Pathways affected {#pathways}

ATM participates in **28 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | curated |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA2/RAD51/RAD51C binding function](https://reactome.org/content/detail/R-HSA-9704646) | curated |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | curated |
| ⚕ [Impaired BRCA2 binding to PALB2](https://reactome.org/content/detail/R-HSA-9709603) | curated |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | curated |
| [Autodegradation of the E3 ubiquitin ligase COP1](https://reactome.org/content/detail/R-HSA-349425) | curated |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | curated |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | curated |
| [Nonhomologous End-Joining (NHEJ)](https://reactome.org/content/detail/R-HSA-5693571) | curated |
| [Pexophagy](https://reactome.org/content/detail/R-HSA-9664873) | curated |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | curated |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | curated |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | curated |
| [Regulation of HSF1-mediated heat shock response](https://reactome.org/content/detail/R-HSA-3371453) | curated |
| [Regulation of TP53 Activity through Methylation](https://reactome.org/content/detail/R-HSA-6804760) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | curated |
| [Regulation of TP53 Degradation](https://reactome.org/content/detail/R-HSA-6804757) | curated |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | curated |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | curated |
| [Sensing of DNA Double Strand Breaks](https://reactome.org/content/detail/R-HSA-5693548) | curated |
| [Stabilization of p53](https://reactome.org/content/detail/R-HSA-69541) | curated |
| [TP53 Regulates Transcription of Caspase Activators and Caspases](https://reactome.org/content/detail/R-HSA-6803207) | curated |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |
| [TP53 Regulates Transcription of Genes Involved in Cytochrome C Release](https://reactome.org/content/detail/R-HSA-6803204) | curated |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** protein serine/threonine kinase activity, DNA-dependent protein kinase activity, 1-phosphatidylinositol-3-kinase activity, identical protein binding, protein-containing complex binding.

**Biological process:** DNA damage checkpoint signaling, pexophagy, double-strand break repair via homologous recombination, DNA double-strand break processing, double-strand break repair, DNA damage response.

## Clinical significance {#significance}

**Likely pathogenic** — review status Single submitter *(criteria provided, single submitter)*.

**Submitter consensus:** unanimous (1/1 Likely pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Neuberg Centre For Genomic Medicine, NCGM | Likely pathogenic | criteria provided, single submitter | clinical testing |  |

## Associated conditions {#conditions}

[ataxia telangiectasia](https://sugi.bio/atlas/disease/ataxia-telangiectasia/).

**Reported phenotype names (ClinVar):** Ataxia-telangiectasia syndrome, AT, COMPLEMENTATION GROUP C, Cerebello-oculocutaneous telangiectasia, Immunodeficiency with ataxia telangiectasia, Ataxia-telangiectasia, complementation group D, Ataxia-telangiectasia, LOUIS-BAR SYNDROME, ATAXIA-TELANGIECTASIA, COMPLEMENTATION GROUP A, ATAXIA-TELANGIECTASIA, FRESNO VARIANT, Ataxia-telangiectasia, complementation group E.

## Similar variants {#similar}

Related ATM variant pages (same residue, condition, or type): [ATM p.Lys892Asn](/variant/atm-p-lys892asn), [ATM p.Lys892Glu](/variant/atm-p-lys892glu), [ATM p.Lys892Thr](/variant/atm-p-lys892thr), [ATM p.Lys892=](/variant/atm-p-lys892), [ATM c.1607+1G>T](/variant/atm-c-1607-plus-1g-t), [ATM c.2251-4A>G](/variant/atm-c-2251-minus-4a-g), [ATM c.2466+5G>C](/variant/atm-c-2466-plus-5g-c), [ATM c.3078-1G>A](/variant/atm-c-3078-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); AlphaMissense (Cheng et al. 2023, © Google DeepMind — CC BY 4.0, built 2026-01-27); REVEL (Ioannidis et al. 2016 — ODbL, built 2026-07-13); SaProt (Su et al. 2023 — MIT, built 2026-10-14); SpliceAI (Illumina — free for non-commercial use, built 2026-10-13); CADD (Rentzsch et al. 2019, University of Washington — free for non-commercial use, built 2026-10-10); Conservation (phyloP/phastCons/GERP) (UCSC hg38 470-way mammal (Hiller Lab) + Ensembl Compara, built 2026-07-12); gnomAD Non-coding Constraint (Gnocchi) (Chen et al. 2024, Broad Institute — CC0, built 2026-10-11); gnomAD Regional Missense Constraint (Broad Institute — CC0, built 2026-10-13); Pangolin (Zeng & Li 2022 — CC BY 4.0, built 2026-10-11); Repeat regions (UCSC — RepeatMasker, TRF, segmental duplications, built 2026-10-11); ClinGen (ClinGen, built 2026-09-22); UniProt (CC BY 4.0); Reactome / GO (CC BY 4.0, built 2026-09-23); MaveDB (per-record license, built 2026-10-11); CIViC (CC0, built 2026-09-22); Orphanet (Orphanet, built 2026-06-12)

*Primary record: NCBI ClinVar (variation 3393422). Classifications reflect these databases as of the page's build date and may change. Free reference use — not medical advice; consult the primary submitters and a clinician.*