# NM_002485.5(NBN):c.798G>T (p.Pro266=)

https://sugi.bio/variant/nbn-p-pro266

## Summary

**NBN p.Pro266= (c.798G>T)** is classified **Likely benign** in NBN (ClinVar, Multiple submitters, 2 submitters; last evaluated 2023-07-14). Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs368786672 · 2 submitters · 2 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the NBN gene that is classified as likely benign — not considered disease-causing, submitted by 2 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 | [NBN](https://sugi.bio/atlas/gene/NBN/) |
| Protein change (HGVS p.) | p.Pro266= |
| Coding change (HGVS c.) | c.798G>T |
| MANE Select transcript | [NM_057091](https://www.ncbi.nlm.nih.gov/nuccore/NM_057091) (variant reported on NM_002485) |
| dbSNP | [rs368786672](https://www.ncbi.nlm.nih.gov/snp/rs368786672/) |
| Variant type | single nucleotide variant |
| Location | chr8:89970462-89970462 (GRCh38) |
| ClinVar | [VCV1104167](https://www.ncbi.nlm.nih.gov/clinvar/variation/1104167/) |

**All HGVS expressions:** `LRG_158:g.19210G>T`, `LRG_158t1:c.798G>T`, `NC_000008.10:g.90982690C>A`, `NC_000008.11:g.89970462C>A`, `NG_008860.1:g.19210G>T`, `NM_001024688.3:c.552G>T`, `NM_002485.4:c.798G>T`, `NM_002485.5:c.798G>T`

## Computational & population evidence {#evidence}

**Concordance:** Mixed / partial computational evidence (see below).

- **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 0.516, GERP -3.53, phastCons 0.844 — weakly conserved position
- CADD: **PHRED 0.893**. 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: **below the reporting threshold**. This position is scored for a different substitution (C>T, Δ0.70 acceptor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code 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}


Curated gene–disease validity (ClinGen):

- **Nijmegen breakage syndrome** — Definitive (AR)
- **hereditary breast carcinoma** — Refuted (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 75.83, 47% of residues very-high.

**5 experimental structure(s)** (PDB): [2ASK](https://www.rcsb.org/structure/2ASK), [2GH0](https://www.rcsb.org/structure/2GH0), [2GYR](https://www.rcsb.org/structure/2GYR), [2GYZ](https://www.rcsb.org/structure/2GYZ), [6Q2S](https://www.rcsb.org/structure/6Q2S).

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

*Describes the biological roles of NBN (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:** NBN's established molecular role includes growth factor activity.


### Pathways affected {#pathways}

NBN participates in **3 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| [RAF/MAP kinase cascade](https://reactome.org/content/detail/R-HSA-5673001) | curated |
| [RET signaling](https://reactome.org/content/detail/R-HSA-8853659) | curated |
| [NCAM1 interactions](https://reactome.org/content/detail/R-HSA-419037) | electronic |

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

**Molecular function:** growth factor activity.

**Biological process:** glial cell-derived neurotrophic factor receptor signaling pathway.

## Clinical significance {#significance}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2023-07-14.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2023-07-14 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-01 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [Nijmegen breakage syndrome](https://sugi.bio/atlas/disease/nijmegen-breakage-syndrome/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Microcephaly, normal intelligence and immunodeficiency, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome, Tumor predisposition, Nijmegen breakage syndrome, Immunodeficiency, microcephaly with normal intelligence, Ataxia telangiectasia variant V1, IMMUNODEFICIENCY, MICROCEPHALY, AND CHROMOSOMAL INSTABILITY.

## Same-residue context {#hotspot}

Residue **266** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [NBN p.Pro266fs](/variant/nbn-p-pro266fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related NBN variant pages (same residue, condition, or type): [NBN p.Pro266Ala](/variant/nbn-p-pro266ala), [NBN p.Pro266Arg](/variant/nbn-p-pro266arg), [NBN p.Pro266Ser](/variant/nbn-p-pro266ser), [NBN p.Pro266Leu](/variant/nbn-p-pro266leu), [NBN p.Pro266fs](/variant/nbn-p-pro266fs), [NBN c.1124+1G>C](/variant/nbn-c-1124-plus-1g-c), [NBN c.1124+2T>G](/variant/nbn-c-1124-plus-2t-g), [NBN c.1397+2T>A](/variant/nbn-c-1397-plus-2t-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-11); 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 2026-07-14); 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 1104167). 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.*