# NM_000059.4(BRCA2):c.8298_8299dup (p.Pro2767fs)

https://sugi.bio/variant/brca2-p-pro2767fs

## Summary

**BRCA2 p.Pro2767fs (c.8298_8299dup)** is classified **Pathogenic** in BRCA2 (ClinVar, Expert panel, 4 submitters; last evaluated 2016-10-18). No gnomAD frequency available for this variant; Associated with breast-ovarian cancer, familial, susceptibility to, 2.

**At a glance:** Pathogenic · review: Expert panel · rsID rs397507973 · 4 submitters · 3 linked conditions · no gnomAD frequency available for this variant

## For patients & families {#patients}

This is a change in the BRCA2 gene that is considered disease-causing, submitted by 4 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.Pro2767fs |
| Coding change (HGVS c.) | c.8298_8299dup |
| MANE Select transcript | [NM_000059](https://www.ncbi.nlm.nih.gov/nuccore/NM_000059) |
| dbSNP | [rs397507973](https://www.ncbi.nlm.nih.gov/snp/rs397507973/) |
| Variant type | Microsatellite |
| Location | chr13:32363497-32363498 (GRCh38) |
| ClinVar | [VCV52541](https://www.ncbi.nlm.nih.gov/clinvar/variation/52541/) |

**All HGVS expressions:** `LRG_293:g.53019AC[3]`, `LRG_293t1:c.8298_8299dup`, `NC_000013.10:g.32937635AC[3]`, `NC_000013.11:g.32363498AC[3]`, `NG_012772.3:g.53019AC[3]`, `NM_000059.3:c.8298_8299dupAC`, `NM_000059.4:c.8298_8299dup`

## 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 -1.009, GERP -4.53 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- 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 18 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 microsatellite 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}

**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 **2767** lies in the 'interaction with sem1' 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.Pro2767fs falls in the interaction with sem1 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 2016-10-18.

**Submitter consensus:** unanimous (4/4 Pathogenic).

**Submission history:** 4 submissions (2015–2023); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2021-06-04 |
| Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Pathogenic | reviewed by expert panel | curation | 2016-10-18 |
| Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Pathogenic | criteria provided, single submitter | clinical testing | 2015-10-02 |
| Ambry Genetics | Pathogenic | criteria provided, single submitter | clinical testing | 2023-12-06 |

## 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/), [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, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome, Hereditary breast and ovarian cancer syndrome, Hereditary breast and ovarian cancer, Hereditary breast and ovarian cancer syndrome (HBOC).

## Same-residue context {#hotspot}

Residue **2767** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BRCA2 p.Pro2767_Leu2768insTer](/variant/brca2-p-pro2767-leu2768inster). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRCA2 variant pages (same residue, condition, or type): [BRCA2 p.Pro2767Arg](/variant/brca2-p-pro2767arg), [BRCA2 p.Pro2767His](/variant/brca2-p-pro2767his), [BRCA2 p.Pro2767Leu](/variant/brca2-p-pro2767leu), [BRCA2 p.Pro2767Thr](/variant/brca2-p-pro2767thr), [BRCA2 p.Pro2767=](/variant/brca2-p-pro2767), [BRCA2 p.Pro2767Ala](/variant/brca2-p-pro2767ala), [BRCA2 p.Pro2767Ser](/variant/brca2-p-pro2767ser), [BRCA2 p.Pro2767_Leu2768insTer](/variant/brca2-p-pro2767-leu2768inster).

### 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 52541). 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.*