# NM_000059.4(BRCA2):c.3863A>G (p.Asn1288Ser)

https://sugi.bio/variant/brca2-p-asn1288ser

## Summary

**BRCA2 p.Asn1288Ser (c.3863A>G)** is classified **Conflicting classifications of pathogenicity** in BRCA2 (ClinVar, Conflicting submitters, 8 submitters; last evaluated 2025-12-21). AlphaMissense: likely benign (0.0765); Very rare (popmax 0.0091%, eas); Associated with hereditary breast ovarian cancer syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs80358630 · 8 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.0091%, eas)

## For patients & families {#patients}

This is a change in the BRCA2 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 8 submitters, and is linked to hereditary breast ovarian cancer 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult, Elderly |
| Clinical trials | 51 registered for this condition — see ClinicalTrials.gov |
| 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/0015010/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.Asn1288Ser |
| Coding change (HGVS c.) | c.3863A>G |
| MANE Select transcript | [NM_000059](https://www.ncbi.nlm.nih.gov/nuccore/NM_000059) |
| dbSNP | [rs80358630](https://www.ncbi.nlm.nih.gov/snp/rs80358630/) |
| Variant type | single nucleotide variant |
| Location | chr13:32338218-32338218 (GRCh38) |
| ClinVar | [VCV462312](https://www.ncbi.nlm.nih.gov/clinvar/variation/462312/) |

**All HGVS expressions:** `LRG_293:g.27739A>G`, `LRG_293t1:c.3863A>G`, `NC_000013.10:g.32912355A>G`, `NC_000013.11:g.32338218A>G`, `NG_012772.3:g.27739A>G`, `NM_000059.4:c.3863A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.0765)
- REVEL 0.108 (moderately benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated
- Conservation: phyloP -0.177, GERP -2.74 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 0.407**. 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 1.03** across the covering region of the MANE Select transcript (32,316,461–32,363,509), spanning 47,048 bp. Chi-square p 0.059. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code 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 **0.0091%** (eas) · FAF95 0.00302% · FAF99 0.00183% · 4/43,950 in the highest group · 4/1,541,790 alleles overall — very rare (popmax 0.0091%, eas).

*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, triplosensitivity 0 (0–3 scale). *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 **1288** lies in the 'interaction with rad51' 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.Asn1288Ser falls in the interaction with rad51 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-12-21.

**Submitter consensus:** conflicting (4 Uncertain significance, 3 Likely benign, 1 Uncertain Significance).

**Submission history:** 8 submissions (2021–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| All of Us Research Program, National Institutes of Health | Uncertain Significance | criteria provided, single submitter | clinical testing | 2023-11-30 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2021-09-22 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2025-04-13 |
| Molecular Pathology, Peter Maccallum Cancer Centre | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-17 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-09-08 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-12-21 |
| University of Washington Department of Laboratory Medicine, University of Washington | Likely benign | criteria provided, single submitter | curation | 2023-03-23 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-01 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary breast ovarian cancer syndrome, Hereditary cancer-predisposing syndrome, Breast-ovarian cancer, familial, susceptibility to, 2, not provided, BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer, Hereditary breast and ovarian cancer syndrome, Hereditary breast and/or ovarian cancer syndrome, Hereditary breast and ovarian cancer syndrome (HBOC), Hereditary breast and ovarian cancer, Breast and ovarian cancer.

## Same-residue context {#hotspot}

Residue **1288** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [BRCA2 p.Asn1288fs](/variant/brca2-p-asn1288fs), [BRCA2 p.Asn1288Ter](/variant/brca2-p-asn1288ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRCA2 variant pages (same residue, condition, or type): [BRCA2 p.Asn1288=](/variant/brca2-p-asn1288), [BRCA2 p.Asn1288Ile](/variant/brca2-p-asn1288ile), [BRCA2 p.Asn1288Asp](/variant/brca2-p-asn1288asp), [BRCA2 p.Asn1288His](/variant/brca2-p-asn1288his), [BRCA2 p.Asn1288fs](/variant/brca2-p-asn1288fs), [BRCA2 p.Asn1288Ter](/variant/brca2-p-asn1288ter), [BRCA2 p.Asn1288del](/variant/brca2-p-asn1288del), [BRCA2 c.316+1G>T](/variant/brca2-c-316-plus-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 462312). 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.*