# NM_000059.4(BRCA2):c.8059G>T (p.Val2687Phe)

https://sugi.bio/variant/brca2-p-val2687phe

## Summary

**BRCA2 p.Val2687Phe (c.8059G>T)** is classified **Uncertain significance** in BRCA2 (ClinVar, Expert panel, 6 submitters; last evaluated 2025-08-18). AlphaMissense: likely pathogenic (0.6901); Very rare (popmax 0.0011%, sas); Associated with BRCA2-related cancer predisposition.

**At a glance:** Uncertain significance · review: Expert panel · rsID rs80359044 · 6 submitters · 4 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.0011%, sas)

## For patients & families {#patients}

This is a change in the BRCA2 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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/) |
| Protein change (HGVS p.) | p.Val2687Phe |
| Coding change (HGVS c.) | c.8059G>T |
| MANE Select transcript | [NM_000059](https://www.ncbi.nlm.nih.gov/nuccore/NM_000059) |
| dbSNP | [rs80359044](https://www.ncbi.nlm.nih.gov/snp/rs80359044/) |
| Variant type | single nucleotide variant |
| Location | chr13:32363261-32363261 (GRCh38) |
| ClinVar | [VCV52491](https://www.ncbi.nlm.nih.gov/clinvar/variation/52491/) |

**All HGVS expressions:** `LRG_293:g.52782G>T`, `LRG_293t1:c.8059G>T`, `NC_000013.10:g.32937398G>T`, `NC_000013.11:g.32363261G>T`, `NG_012772.3:g.52782G>T`, `NM_000059.4:c.8059G>T`, `U43746.1:n.8287G>T`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.6901)
- REVEL 0.811 (moderately pathogenic-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this damaging
- Conservation: phyloP 1.905, GERP 0.394, phastCons 0.998 — weakly conserved position
- AlphaMissense ranks this among the **top 5%** most-pathogenic-predicted substitutions in BRCA2 (of 20,162 modeled).
- CADD: **PHRED 23.1**. 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 **0.0011%** (sas) · 1/91,082 in the highest group · 1/1,461,808 alleles overall — very rare (popmax 0.0011%, sas).

*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 **2687** 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.Val2687Phe 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}

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

**Submitter consensus:** conflicting (3 Uncertain significance, 2 Likely pathogenic, 1 Uncertain Significance).

**Submission history:** 6 submissions (2003–2025); classifications have differed over time.

**ClinGen expert panel:** Uncertain Significance — ENIGMA BRCA1 and BRCA2 VCEP (BRCA2-related cancer predisposition). *Expert-panel curated (ACMG); the highest ClinVar review tier.*
**Applied ACMG criteria (met):** `PS3`, `PP3`.
*Considered but not met:* `PM2_Supporting`, `PP4`, `BS1_Supporting`, `BP5`, `BP7_Strong`, `BA1`.
Inheritance: Autosomal dominant inheritance.

> **Curation rationale (ClinGen, verbatim):** The c.8059G>T variant in BRCA2 is a missense variant predicted to cause substitution of Valine by Phenylalanine at amino acid 2687 (p.(Val2687Phe)). This variant is present in gnomAD v2.1 (exomes only, non-cancer subset) or gnomAD v3.1 (non-cancer subset) but is below the ENIGMA BRCA1/2 VCEP threshold >0.00002 for BS1_Supporting (PM2_Supporting, BS1, and BA1 are not met). This BRCA2 missense variant is within a key functional domain and the computational predictor BayesDel (noAF) gives a score of 0.37, above the recommended threshold of 0.30 for prediction of impact on BRCA2 function via protein change. A SpliceAI score of 0 predicts no impact on splicing (score threshold <0.10) (PP3 met). Reported by three calibrated studies to exhibit protein function similar to pathogenic control variants (PMIDs:38417439, 39779857, 39779848) (PS3 met). mRNA experimental analysis indicates no impact on splicing (Internal lab contributor) but is not applied as strong evidence against pathogenicity since missense impact has not been excluded (BP7_Strong (RNA) not met). Multifactorial likelihood ratio analysis using clinically calibrated data produced a combined LR for this variant of 1.42 (based on Family History LR=1.42), which is above the ENIGMA BRCA1/2 VCEP threshold for BP5 (>0.48) and below PP4 (<2.08) (BP5 and PP4 not met; PMID: 31853058). In summary, this variant meets the criteria to be classified as a Variant of uncertain significance for BRCA2-related cancer predisposition based on the ACMG/AMP criteria applied as specified by the ENIGMA BRCA1/2 VCEP (PS3, PP3).
*Source: https://cspec.clinicalgenome.org/cspec/ui/svi/affiliation/50087 · approved 2025-08-18 · [ClinGen Evidence Repository](https://erepo.genome.network/evrepo/ui/classification/aa16180c-69d0-4d51-9b11-ecfb4e829052).*
*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 |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-07-21 |
| PreventionGenetics, part of Exact Sciences | Likely pathogenic | criteria provided, single submitter | clinical testing | 2023-01-19 |
| Breast Cancer Information Core (BIC) (BRCA2) | Uncertain significance | no assertion criteria provided | clinical testing | 2003-12-23 |
| Ambry Genetics | Likely pathogenic | criteria provided, single submitter | clinical testing | 2024-03-06 |
| ClinGen ENIGMA BRCA1 and BRCA2 Variant Curation Expert Panel, ClinGen | Uncertain Significance | reviewed by expert panel | curation | 2025-08-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-09-17 |

## 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, not provided, Hereditary cancer-predisposing syndrome, Hereditary breast ovarian cancer syndrome, BRCA2-related disorder, Neoplastic Syndromes, Hereditary, Tumor predisposition, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome.

## Same-residue context {#hotspot}

Residue **2687** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [BRCA2 p.Val2687fs](/variant/brca2-p-val2687fs), [BRCA2 p.Val2687_Leu2688del](/variant/brca2-p-val2687-leu2688del). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRCA2 variant pages (same residue, condition, or type): [BRCA2 p.Val2687=](/variant/brca2-p-val2687), [BRCA2 p.Val2687Ala](/variant/brca2-p-val2687ala), [BRCA2 p.Val2687Ile](/variant/brca2-p-val2687ile), [BRCA2 p.Val2687fs](/variant/brca2-p-val2687fs), [BRCA2 p.Val2687_Leu2688del](/variant/brca2-p-val2687-leu2688del), [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).

### 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 52491). 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.*