# NM_000051.4(ATM):c.3710T>G (p.Ile1237Ser)

https://sugi.bio/variant/atm-p-ile1237ser

## Summary

**ATM p.Ile1237Ser (c.3710T>G)** is classified **Uncertain significance** in ATM (ClinVar, Multiple submitters, 6 submitters; last evaluated 2025-11-11). AlphaMissense: likely benign (0.1529); Very rare (popmax 0.000271%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs786202897 · 6 submitters · 2 linked conditions · AlphaMissense likely benign · very rare (popmax 0.000271%, nfe)

## For patients & families {#patients}

This is a change in the ATM gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 6 submitters, and is linked to hereditary neoplastic syndrome.

*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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/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.Ile1237Ser |
| Coding change (HGVS c.) | c.3710T>G |
| MANE Select transcript | [NM_000051](https://www.ncbi.nlm.nih.gov/nuccore/NM_000051) |
| dbSNP | [rs786202897](https://www.ncbi.nlm.nih.gov/snp/rs786202897/) |
| Variant type | single nucleotide variant |
| Location | chr11:108282843-108282843 (GRCh38) |
| ClinVar | [VCV186372](https://www.ncbi.nlm.nih.gov/clinvar/variation/186372/) |

**All HGVS expressions:** `LRG_135:g.65012T>G`, `LRG_135t1:c.3710T>G`, `NC_000011.10:g.108282843T>G`, `NC_000011.9:g.108153570T>G`, `NG_009830.1:g.65012T>G`, `NM_000051.4:c.3710T>G`, `NM_001351834.2:c.3710T>G`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **tolerated** — a triage signal, not a reclassification.

- AlphaMissense **likely benign** (0.1529)
- REVEL 0.102 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- SpliceAI predicts **acceptor gain** (Δ 0.70) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 3.464, GERP -0.335, phastCons 1 — highly conserved (differs from AlphaMissense)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 27.4**. 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.*
- Regional missense constraint: **o/e 0.99** across the covering region of the MANE Select transcript (108,227,625–108,293,379), spanning 65,754 bp. Chi-square p 0.75. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.14**, donor loss **0.00**, acceptor gain **0.70**, donor gain **0.00**. Largest is acceptor gain.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.70**, donor gain **0.00**.
- Pangolin: Δ**0.54** (gain), gain 0.54 / loss 0.00. Agrees with SpliceAI. 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 (gnomAD v4.1): grpmax **0.000271%** (nfe) · FAF95 7.2e-05% · FAF99 2e-05% · 3/1,106,526 in the highest group · 3/1,529,924 alleles overall — very rare (popmax 0.000271%, nfe).

*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 **1237** lies in a UniProt-annotated variant site (in at); an α-helix; a UniProt-annotated variant site (in at; uncertain significance); a UniProt-annotated variant site (in at; uncertain significance; increases protein abundance).

**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}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-11-11.

**Submitter consensus:** unanimous (6/6 Uncertain significance).

**Submission history:** 6 submissions (2019–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-04-15 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2021-03-26 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-09-03 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-11-11 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-01-25 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-05 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [ataxia telangiectasia](https://sugi.bio/atlas/disease/ataxia-telangiectasia/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, not provided, Ataxia-telangiectasia syndrome, not specified, none provided, AllHighlyPenetrant, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary neoplastic syndrome.

## Similar variants {#similar}

Related ATM variant pages (same residue, condition, or type): [ATM p.Ile1237Phe](/variant/atm-p-ile1237phe), [ATM p.Ile1237Thr](/variant/atm-p-ile1237thr), [ATM p.Ile1237Leu](/variant/atm-p-ile1237leu), [ATM p.Ile1237Val](/variant/atm-p-ile1237val), [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 186372). 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.*