# NM_000059.4(BRCA2):c.631+4A>G

https://sugi.bio/variant/brca2-c-631-plus-4a-g

## Summary

**BRCA2 c.631+4A>G** is classified **Likely pathogenic** in BRCA2 (ClinVar, Expert panel, 6 submitters; last evaluated 2025-08-18). Very rare (popmax 0.00168%, amr); Associated with BRCA2-related cancer predisposition.

**At a glance:** Likely pathogenic · review: Expert panel · rsID rs397507841 · 6 submitters · 4 linked conditions · very rare (popmax 0.00168%, amr)

## For patients & families {#patients}

This is a change in the BRCA2 gene that is considered likely disease-causing, submitted by 6 submitters, and is linked to BRCA2-related cancer predisposition.

*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.*

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0026409/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BRCA2](https://sugi.bio/atlas/gene/BRCA2/) |
| Coding change (HGVS c.) | c.631+4A>G |
| MANE Select transcript | [NM_000059](https://www.ncbi.nlm.nih.gov/nuccore/NM_000059) |
| dbSNP | [rs397507841](https://www.ncbi.nlm.nih.gov/snp/rs397507841/) |
| Variant type | single nucleotide variant |
| Location | chr13:32326617-32326617 (GRCh38) |
| ClinVar | [VCV52056](https://www.ncbi.nlm.nih.gov/clinvar/variation/52056/) |

**All HGVS expressions:** `LRG_293:g.16138A>G`, `LRG_293t1:c.631+4A>G`, `NC_000013.10:g.32900754A>G`, `NC_000013.11:g.32326617A>G`, `NG_012772.3:g.16138A>G`, `NM_000059.4:c.631+4A>G`

## Computational & population evidence {#evidence}

**Concordance:** 1 independent predictor **concordant** with the ClinVar classification.

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.71) — consistent with the pathogenic call
- Conservation: phyloP 6.67, GERP 1.09, phastCons 1 — highly conserved position (PP3-type support)
- CADD: **PHRED 3.846**. 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.*
- Splice region: **donor splice region (+4, within the first 6 intronic nt)** — inside the zone ClinGen GN167 excludes from BP7, so this variant must not be called benign merely for being synonymous or intronic.
- Non-coding constraint (Gnocchi): **Z 1.05**, o/e 0.92 (1 kb window 32,326,000–32,327,000). A higher Z means the window carries less variation than expected. Describes the 1 kb window, not this allele. No ClinGen expert panel references Gnocchi and no ACMG-calibrated threshold exists for it. *Descriptive; no cut-point applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.71**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 4 bp away.
  These are **raw** scores. Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — can legitimately show 0 where this shows a score; the masked figures are not available for this record.
- Pangolin: Δ**0.58** (loss), gain 0.03 / loss 0.58. Agrees with SpliceAI. An independent predictor to SpliceAI — a different model trained on different data. *Descriptive; ClinGen's SVI calibration covers SpliceAI, not Pangolin, so no ACMG code is assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00168%** (amr) · 1/59,580 in the highest group · 1/1,412,984 alleles overall — very rare (popmax 0.00168%, amr).

*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}


**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. 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}

**Likely pathogenic** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2025-08-18.

**Submitter consensus:** conflicting (4 Likely pathogenic, 1 Likely Pathogenic, 1 Pathogenic).

**Submission history:** 6 submissions (2015–2026); classifications have differed over time.

**ClinGen expert panel:** Likely Pathogenic — ENIGMA BRCA1 and BRCA2 VCEP (BRCA2-related cancer predisposition). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PM2_Supporting`, `PVS1`.
*Considered but not met:* `PP3`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.631+4A>G variant is an intronic variant occurring in intron 7 of the BRCA2 gene. This variant is absent from gnomAD v2.1 (exomes only, non-cancer subset, read depth ≥25) and gnomAD v3.1 (non-cancer subset, read depth ≥25) (PM2_Supporting met). This BRCA2 intronic variant is located outside of the native donor and acceptor 1,2 splice sites, and has a SpliceAI score of 0.71, predicting an impact on splicing (score threshold ≥0.2) (PP3 not applied because a PVS1 code is met). This variant is reported to result in aberrant mRNA splicing. RNAseq, minigene and RT-PCR demonstrated that the variant impacts splicing by exon skipping (PMIDs: 20455026, 31143303). Preliminary code strength determined by comparison of results to PVS1 decision tree and assessment of mRNA splicing data (PVS1 (RNA) met). The percent reference (full-length, FL) and aberrant transcripts produced from the variant allele using allele specific quantitative assessment with Capillary electrophoresis was determined to be full-length (0%) / exon skipping (100%). Final code strength determined by the rubric: PVS1 (RNA). In summary, this variant meets the criteria to be classified as a Likely pathogenic variant for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PM2_Supporting, PVS1 (RNA)).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50087 · approved 2025-08-18 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/c606ba33-bde7-4122-bd73-7cd241b13573).*
*These are ClinGen's applied codes, reported verbatim — Sugi Variant does not re-tally or combine them into its own classification.*

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| AiLife Diagnostics, AiLife Diagnostics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2020-04-01 |
| Department of Medical Genetics, Oslo University Hospital | Likely pathogenic | criteria provided, single submitter | clinical testing | 2017-07-17 |
| ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen | Likely Pathogenic | reviewed by expert panel | curation | 2025-08-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely pathogenic | criteria provided, single submitter | clinical testing | 2022-08-22 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2026-06-12 |
| Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge | Pathogenic | criteria provided, single submitter | clinical testing | 2015-10-02 |

## Associated conditions {#conditions}

[BRCA2-related cancer predisposition](https://sugi.bio/atlas/disease/brca2-related-cancer-predisposition/), [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):** BRCA2-related cancer predisposition, Breast-ovarian cancer, familial, susceptibility to, 2, Hereditary breast ovarian cancer syndrome, not provided, Hereditary cancer-predisposing syndrome, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, Tumor predisposition, Hereditary Cancer Syndrome, none provided.

## Similar variants {#similar}

Related BRCA2 variant pages (same residue, condition, or type): [BRCA2 c.316+1G>T](/variant/brca2-c-316-plus-1g-t), [BRCA2 c.316+2T>C](/variant/brca2-c-316-plus-2t-c), [BRCA2 c.316+5G>A](/variant/brca2-c-316-plus-5g-a), [BRCA2 c.316+5G>C](/variant/brca2-c-316-plus-5g-c), [BRCA2 c.475+1G>A](/variant/brca2-c-475-plus-1g-a), [BRCA2 c.475+1G>T](/variant/brca2-c-475-plus-1g-t), [BRCA2 c.476-2A>G](/variant/brca2-c-476-minus-2a-g), [BRCA2 c.517-2A>G](/variant/brca2-c-517-minus-2a-g).

### 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 52056). 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.*