# NM_002485.5(NBN):c.1999T>C (p.Ser667Pro)

https://sugi.bio/variant/nbn-p-ser667pro

## Summary

**NBN p.Ser667Pro (c.1999T>C)** is classified **Conflicting classifications of pathogenicity** in NBN (ClinVar, Conflicting submitters, 14 submitters; last evaluated 2025-07-13). AlphaMissense: likely benign (0.0751); Ultra-rare (popmax 0.05%, amr); Associated with Nijmegen breakage syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs587780091 · 14 submitters · 5 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.05%, amr)

## For patients & families {#patients}

This is a change in the NBN gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 14 submitters, and is linked to Nijmegen breakage 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 | 3 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0003904/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.Ser667Pro |
| Coding change (HGVS c.) | c.1999T>C |
| MANE Select transcript | [NM_057091](https://www.ncbi.nlm.nih.gov/nuccore/NM_057091) (variant reported on NM_002485) |
| dbSNP | [rs587780091](https://www.ncbi.nlm.nih.gov/snp/rs587780091/) |
| Variant type | single nucleotide variant |
| Location | chr8:89946211-89946211 (GRCh38) |
| ClinVar | [VCV127863](https://www.ncbi.nlm.nih.gov/clinvar/variation/127863/) |

**All HGVS expressions:** `LRG_158:g.43461T>C`, `LRG_158t1:c.1999T>C`, `NC_000008.10:g.90958439A>G`, `NC_000008.11:g.89946211A>G`, `NG_008860.1:g.43461T>C`, `NM_001024688.3:c.1753T>C`, `NM_002485.5:c.1999T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0751)
- REVEL 0.019 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -6.14 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 0.294, GERP -3.83, phastCons 0.421 — weakly conserved position
- CADD: **PHRED 6.808**. 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: **not assessed** — no allele at this position is in our SpliceAI release, either because it lies outside the scored MANE transcript scope or because every allele is below Δ0.2. We cannot tell which, so this claims neither; absence is not evidence against a splicing effect.
- Population frequency (gnomAD v4.1): grpmax **0.05%** (amr) · FAF95 0.036% · FAF99 0.0312% · 30/59,964 in the highest group · 158/1,599,276 alleles overall — ultra-rare (popmax 0.05%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.05% | 1,999 |
| Remaining individuals (not grpmax-eligible) | 0.0129% | 7,746 |
| European (non-Finnish) | 0.01% | 9,975 |
| African / African-American | 0.00402% | 24,875 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-07-13.

**Submitter consensus:** conflicting (11 Uncertain significance, 3 Likely benign).

**Submission history:** 14 submissions (2017–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-05-23 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2019-02-11 |
| Natera, Inc. | Uncertain significance | no assertion criteria provided | clinical testing | 2020-03-11 |
| Sema4, Sema4 | Uncertain significance | criteria provided, single submitter | curation | 2021-12-23 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-10-05 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-06 |
| PreventionGenetics, part of Exact Sciences | Uncertain significance | no assertion criteria provided | clinical testing | 2023-12-20 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-17 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2021-05-01 |
| Genome-Nilou Lab | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-11-07 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-01-09 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-07-22 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-09-19 |
| Laboratorio de I+D, Fundación Centro Médico de Asturias | Likely benign | criteria provided, single submitter | clinical testing | 2025-07-13 |

## Associated conditions {#conditions}

[Nijmegen breakage syndrome](https://sugi.bio/atlas/disease/nijmegen-breakage-syndrome/), [hereditary breast ovarian cancer syndrome](https://sugi.bio/atlas/disease/hereditary-breast-ovarian-cancer-syndrome/), [acute lymphoblastic leukemia](https://sugi.bio/atlas/disease/acute-lymphoblastic-leukemia/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [aplastic anemia](https://sugi.bio/atlas/disease/aplastic-anemia/).

**Reported phenotype names (ClinVar):** Microcephaly, normal intelligence and immunodeficiency, Hereditary cancer-predisposing syndrome, not provided, Acute lymphoid leukemia, Aplastic anemia, not specified, NBN-related disorder, Hereditary breast ovarian cancer syndrome, NBN-related condition, Nijmegen breakage syndrome.

## Same-residue context {#hotspot}

Residue **667** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [NBN p.Ser667fs](/variant/nbn-p-ser667fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related NBN variant pages (same residue, condition, or type): [NBN p.Ser667=](/variant/nbn-p-ser667), [NBN p.Ser667Phe](/variant/nbn-p-ser667phe), [NBN p.Ser667fs](/variant/nbn-p-ser667fs), [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), [NBN c.171+1G>A](/variant/nbn-c-171-plus-1g-a), [NBN c.172-1G>T](/variant/nbn-c-172-minus-1g-t).

### 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 127863). 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.*