# NM_000051.4(ATM):c.2429del (p.Lys810fs)

https://sugi.bio/variant/atm-p-lys810fs

## Summary

**ATM p.Lys810fs (c.2429del)** is classified **Pathogenic** in ATM (ClinVar, Single submitter, 1 submitter; last evaluated 2022-08-09). No gnomAD frequency available for this variant; Associated with ataxia telangiectasia.

**At a glance:** Pathogenic · review: Single submitter · rsID rs2497419319 · 1 submitter · 1 linked condition · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the ATM gene that is reported as disease-causing, but on limited review, 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.Lys810fs |
| Coding change (HGVS c.) | c.2429del |
| MANE Select transcript | [NM_000051](https://www.ncbi.nlm.nih.gov/nuccore/NM_000051) |
| dbSNP | [rs2497419319](https://www.ncbi.nlm.nih.gov/snp/rs2497419319/) |
| Variant type | Deletion |
| Location | chr11:108259036-108259036 (GRCh38) |
| ClinVar | [VCV2023312](https://www.ncbi.nlm.nih.gov/clinvar/variation/2023312/) |

**All HGVS expressions:** `LRG_135:g.41207del`, `LRG_135t1:c.2429del`, `NC_000011.10:g.108259038del`, `NC_000011.9:g.108129765del`, `NG_009830.1:g.41207del`, `NM_000051.4:c.2429del`, `NM_001351834.2:c.2429del`

## 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 7.627, GERP 2.53, phastCons 1 — highly conserved position (PP3-type support)
- Molecular consequence: **frameshift** — 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 16 of 63**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.
- Population frequency: **no gnomAD frequency available for this variant** — rarity (ACMG PM2) and BA1/BS1 cannot be assessed for this variant.

*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 **810** 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2022-08-09.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2022-08-09 |

## Associated conditions {#conditions}

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

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

## Same-residue context {#hotspot}

Residue **810** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [ATM p.Lys810Ter](/variant/atm-p-lys810ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related ATM variant pages (same residue, condition, or type): [ATM p.Lys810Glu](/variant/atm-p-lys810glu), [ATM p.Lys810=](/variant/atm-p-lys810), [ATM p.Lys810Met](/variant/atm-p-lys810met), [ATM c.2639-22_2639-20del](/variant/atm-c-2639-minus-22-2639-minus-20del), [ATM p.Ala2045_Leu2046insTer](/variant/atm-p-ala2045-leu2046inster), [ATM p.Asn1719fs](/variant/atm-p-asn1719fs), [ATM p.Asp130fs](/variant/atm-p-asp130fs), [ATM p.Glu1267_Val1268insTer](/variant/atm-p-glu1267-val1268inster).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-06); 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 2023312). 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.*