# NM_000059.4(BRCA2):c.26del (p.Pro9fs)

https://sugi.bio/variant/brca2-p-pro9fs

## Summary

**BRCA2 p.Pro9fs (c.26del)** is classified **Pathogenic** in BRCA2 (ClinVar, Expert panel, 22 submitters; last evaluated 2016-04-22). Very rare (popmax 0.000254%, nfe); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

**At a glance:** Pathogenic · review: Expert panel · rsID rs80359343 · 22 submitters · 4 linked conditions · very rare (popmax 0.000254%, nfe)

## For patients & families {#patients}

This is a change in the BRCA2 gene that is considered disease-causing, submitted by 22 submitters, and is linked to breast-ovarian cancer, familial, susceptibility to, 2.

*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 dominant |
| Age of onset (of this condition) | Adult, Elderly |
| Diagnostic panels | BRCA2 is a diagnostic-grade gene on 33 Genomics England panels |

**Commonly reported features of Hereditary breast and/or ovarian cancer syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the fallopian tube — Very frequent (99-80%)
- Primary peritoneal carcinoma — Very frequent (99-80%)
- Ovarian neoplasm — Very frequent (99-80%)
- Breast carcinoma — Frequent (79-30%)
- Melanoma — Occasional (29-5%)
- Neoplasm of the pancreas — Occasional (29-5%)
- Prostate cancer — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0027821/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BRCA2](https://sugi.bio/atlas/gene/BRCA2/) |
| Protein change (HGVS p.) | p.Pro9fs |
| Coding change (HGVS c.) | c.26del |
| MANE Select transcript | [NM_000059](https://www.ncbi.nlm.nih.gov/nuccore/NM_000059) |
| dbSNP | [rs80359343](https://www.ncbi.nlm.nih.gov/snp/rs80359343/) |
| Variant type | Deletion |
| Location | chr13:32316485-32316485 (GRCh38) |
| ClinVar | [VCV51330](https://www.ncbi.nlm.nih.gov/clinvar/variation/51330/) |

**All HGVS expressions:** `LRG_293:g.6007del`, `NC_000013.10:g.32890623del`, `NC_000013.11:g.32316486del`, `NG_012772.3:g.6007del`, `NG_017006.2:g.3879del`, `NM_000059.3:c.26delC`, `NM_000059.4:c.26del`, `U43746.1:n.254delC`

## 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 0.467, GERP -3.97, phastCons 0.982 — weakly conserved position
- 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 2 of 27**, 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 (gnomAD v4.1): grpmax **0.000254%** (nfe) · FAF95 6.8e-05% · FAF99 1.9e-05% · 3/1,179,898 in the highest group · 3/1,613,836 alleles overall — very rare (popmax 0.000254%, 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}

**BRCA2** population constraint: LOEUF 0.803, pLI 6.5274e-44, missense-Z 1.0218; 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):

- **Fanconi anemia complementation group D1** — Definitive (AR)
- **BRCA2-related cancer predisposition** — Definitive (AD)

## Protein context {#protein}

Residue **9** lies in the 'interaction with palb2' region.

**14 experimental structure(s)** (PDB): [1N0W](https://www.rcsb.org/structure/1N0W), [3EU7](https://www.rcsb.org/structure/3EU7), [6GY2](https://www.rcsb.org/structure/6GY2), [6HQU](https://www.rcsb.org/structure/6HQU), [7BDX](https://www.rcsb.org/structure/7BDX), [7LDG](https://www.rcsb.org/structure/7LDG) — incl. mutant structure 6HQU.

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

*Describes the biological roles of BRCA2 (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:** BRCA2's established molecular role includes protease binding. p.Pro9fs falls in the interaction with palb2 region. In Reactome, BRCA2 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):** BRCA2 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}

BRCA2 participates in **14 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 |
| ⚕ [Impaired BRCA2 binding to SEM1 (DSS1)](https://reactome.org/content/detail/R-HSA-9763198) | curated |
| ⚕ [Impaired BRCA2 translocation to the nucleus](https://reactome.org/content/detail/R-HSA-9709275) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [HDR through MMEJ (alt-NHEJ)](https://reactome.org/content/detail/R-HSA-5685939) | curated |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | curated |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | 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 |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | electronic |

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

**Molecular function:** protease binding, single-stranded DNA binding, histone H3 acetyltransferase activity, histone H4 acetyltransferase activity, identical protein binding, gamma-tubulin binding.

**Biological process:** double-strand break repair via homologous recombination, nucleotide-excision repair, double-strand break repair, negative regulation of mammary gland epithelial cell proliferation, positive regulation of DNA-templated transcription, centrosome duplication.

## Clinical significance {#significance}

**Pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2016-04-22.

**Submitter consensus:** conflicting (21 Pathogenic, 1 pathogenic).

**Submission history:** 22 submissions (2004–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Sharing Clinical Reports Project (SCRP) | Pathogenic | no assertion criteria provided | clinical testing | 2007-02-15 |
| Color Diagnostics, LLC DBA Color Health | Pathogenic | criteria provided, single submitter | clinical testing | 2020-01-15 |
| Sema4, Sema4 | Pathogenic | criteria provided, single submitter | curation | 2021-09-02 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | pathogenic | criteria provided, single submitter | clinical testing | 2024-02-21 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Pathogenic | criteria provided, single submitter | clinical testing | 2025-05-15 |
| Breast Cancer Information Core (BIC) (BRCA2) | Pathogenic | no assertion criteria provided | clinical testing | 2004-02-20 |
| Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Pathogenic | reviewed by expert panel | curation | 2016-04-22 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-04-23 |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Pathogenic | criteria provided, single submitter | clinical testing | 2019-08-21 |
| GeneDx | Pathogenic | criteria provided, single submitter | clinical testing | 2023-06-01 |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-31 |
| Cambridge Genomics Laboratory, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Pathogenic | criteria provided, single submitter | clinical testing | 2026-01-29 |
| Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto | Pathogenic | no assertion criteria provided | research | 2014-01-31 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Pathogenic | no assertion criteria provided | clinical testing |  |
| Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Pathogenic | criteria provided, single submitter | clinical testing | 2015-10-02 |
| BRCAlab, Lund University | Pathogenic | no assertion criteria provided | clinical testing | 2020-03-02 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2022-09-06 |
| PreventionGenetics, part of Exact Sciences | Pathogenic | no assertion criteria provided | clinical testing | 2024-05-08 |
| Genomics and Molecular Medicine Service, East Genomic Laboratory Hub, NHS Genomic Medicine Service | Pathogenic | criteria provided, single submitter | clinical testing | 2024-09-25 |
| Counsyl | Pathogenic | no assertion criteria provided | clinical testing | 2016-08-31 |
| Revvity Omics, Revvity | Pathogenic | criteria provided, single submitter | clinical testing | 2019-06-12 |
| Genetics Laboratory, Great Ormond Street Hospital NHS Foundation Trust, North Thames Genomic Laboratory Hub | Pathogenic | criteria provided, single submitter | clinical testing | 2026-04-24 |

## Associated conditions {#conditions}

[breast-ovarian cancer, familial, susceptibility to, 2](https://sugi.bio/atlas/disease/breast-ovarian-cancer-familial-susceptibility-to-2/), [hereditary breast ovarian cancer syndrome](https://sugi.bio/atlas/disease/hereditary-breast-ovarian-cancer-syndrome/), [breast cancer](https://sugi.bio/atlas/disease/breast-cancer/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/).

**Reported phenotype names (ClinVar):** Breast-ovarian cancer, familial, susceptibility to, 2, Hereditary breast ovarian cancer syndrome, Hereditary cancer-predisposing syndrome, not provided, Malignant tumor of breast, Breast and/or ovarian cancer, Inherited breast cancer and ovarian cancer, BRCA2-related disorder, BRCA2-related condition, BRCA2-related disorders.

## Similar variants {#similar}

Related BRCA2 variant pages (same residue, condition, or type): [BRCA2 p.Pro9=](/variant/brca2-p-pro9), [BRCA2 p.Pro9Ser](/variant/brca2-p-pro9ser), [BRCA2 p.Pro9Arg](/variant/brca2-p-pro9arg), [BRCA2 p.Pro9Leu](/variant/brca2-p-pro9leu), [BRCA2 c.316+4del](/variant/brca2-c-316-plus-4del), [BRCA2 c.5217_5224del](/variant/brca2-c-5217-5224del), [BRCA2 c.68-?_316+?del](/variant/brca2-c-68-minus-316-plus-del), [BRCA2 c.7008-?_7805+?del](/variant/brca2-c-7008-minus-7805-plus-del).

### 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 51330). 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.*