# NM_000059.4(BRCA2):c.1365A>G (p.Ser455=)

https://sugi.bio/variant/brca2-p-ser455

## Summary

**BRCA2 p.Ser455= (c.1365A>G)** is classified **Benign** in BRCA2 (ClinVar, Expert panel, 32 submitters; last evaluated 2015-01-12). Common (popmax 11.7%, eas) — too common for a highly-penetrant pathogenic allele; Associated with breast-ovarian cancer, familial, susceptibility to, 2.

**At a glance:** Benign · review: Expert panel · rsID rs1801439 · 32 submitters · 5 linked conditions · common (popmax 11.7%, eas) — too common for a highly-penetrant pathogenic allele

## For patients & families {#patients}

This is a change in the BRCA2 gene that is classified as benign — not considered disease-causing, submitted by 32 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.Ser455= |
| Coding change (HGVS c.) | c.1365A>G |
| MANE Select transcript | [NM_000059](https://www.ncbi.nlm.nih.gov/nuccore/NM_000059) |
| dbSNP | [rs1801439](https://www.ncbi.nlm.nih.gov/snp/rs1801439/) |
| Variant type | single nucleotide variant |
| Location | chr13:32332843-32332843 (GRCh38) |
| ClinVar | [VCV125943](https://www.ncbi.nlm.nih.gov/clinvar/variation/125943/) |

**All HGVS expressions:** `LRG_293:g.22364A>G`, `LRG_293t1:c.1365A>G`, `NC_000013.10:g.32906980A>G`, `NC_000013.11:g.32332843A>G`, `NG_012772.3:g.22364A>G`, `NM_000059.4:c.1365A>G`, `U43746.1:n.1593A>G`

## Computational & population evidence {#evidence}

**Concordance:** Evidence sources **disagree** — common (popmax 11.7%, eas) — too common for a highly-penetrant pathogenic allele.

- **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 1.566, GERP -1.63, phastCons 0.708 — weakly conserved position
- CADD: **PHRED 6.0**. 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.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for BRCA2 (1,318 scored positions, the nearest 95 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- Population frequency (gnomAD v4.1): grpmax **11.7%** (eas) · FAF95 11.4% · FAF99 11.3% · 5,236/44,860 in the highest group · 67,606/1,611,544 alleles overall — common (popmax 11.7%, eas) — too common for a highly-penetrant pathogenic allele.

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 11.7% | 9 |
| South Asian | 11.5% | 9 |
| Admixed American | 8.05% | 12 |
| Middle Eastern | 5.43% | 18 |
| Remaining individuals (not grpmax-eligible) | 4.57% | 22 |
| Ashkenazi Jewish (not grpmax-eligible) | 4.15% | 24 |
| European (non-Finnish) | 3.42% | 29 |
| Amish (not grpmax-eligible) | 2.63% | 38 |
| African / African-American | 2.09% | 48 |
| Finnish (not grpmax-eligible) | 1.51% | 66 |

*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}


**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}

**Benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2015-01-12.

**Submitter consensus:** unanimous (34/34 Benign).

**Submission history:** 34 submissions (2002–2026); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Sharing Clinical Reports Project (SCRP) | Benign | no assertion criteria provided | clinical testing | 2011-03-15 |
| PreventionGenetics, part of Exact Sciences | Benign | criteria provided, single submitter | clinical testing |  |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Benign | criteria provided, single submitter | clinical testing | 2023-07-07 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Benign | criteria provided, single submitter | clinical testing | 2025-03-04 |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Benign | criteria provided, single submitter | clinical testing | 2025-02-01 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Benign | criteria provided, single submitter | clinical testing | 2025-07-31 |
| Breast Cancer Information Core (BIC) (BRCA2) | Benign | no assertion criteria provided | clinical testing | 2002-05-29 |
| Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Benign | reviewed by expert panel | curation | 2015-01-12 |
| Color Diagnostics, LLC DBA Color Health | Benign | criteria provided, single submitter | clinical testing | 2015-03-31 |
| Baylor Genetics | Benign | criteria provided, single submitter | clinical testing | 2017-02-23 |
| Cancer Genetics and Genomics Laboratory, British Columbia Cancer Agency | Benign | criteria provided, single submitter | clinical testing | 2017-04-18 |
| GeneKor MSA | Benign | criteria provided, single submitter | clinical testing | 2017-11-01 |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Benign | criteria provided, single submitter | clinical testing | 2015-09-21 |
| Mayo Clinic Laboratories, Mayo Clinic | Benign | no assertion criteria provided | clinical testing | 2017-03-06 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics Laboratory, Department of Pathology, Netherlands Cancer Institute | Benign | no assertion criteria provided | clinical testing |  |
| National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Benign | criteria provided, single submitter | clinical testing | 2022-04-19 |
| Genetics Program, Instituto Nacional de Cancer | Benign | criteria provided, single submitter | research | 2021-11-01 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2014-01-13 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2019-05-07 |
| Breakthrough Genomics, Breakthrough Genomics | Benign | criteria provided, single submitter | not provided |  |
| GreenArray Genomic Research & Solutions of Accurate Diagnostic Private Limited | Benign | criteria provided, single submitter | clinical testing |  |
| Counsyl | Benign | no assertion criteria provided | literature only | 2014-01-02 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| Blueprint Genetics | Benign | criteria provided, single submitter | clinical testing | 2024-11-27 |
| Molecular Genetics Laboratory, University of Michigan | Benign | criteria provided, single submitter | clinical testing | 2014-11-03 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2013-09-27 |
| Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen | Benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, University Medical Center Utrecht | Benign | criteria provided, single submitter | clinical testing | 2014-10-10 |
| Illumina Laboratory Services, Illumina | Benign | criteria provided, single submitter | clinical testing | 2018-01-12 |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Benign | no assertion criteria provided | clinical testing |  |
| Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+ | Benign | no assertion criteria provided | clinical testing |  |
| Eurofins Ntd Llc (ga) | Benign | criteria provided, single submitter | clinical testing | 2015-06-30 |

## 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/), [Fanconi anemia complementation group D1](https://sugi.bio/atlas/disease/fanconi-anemia-complementation-group-d1/), [hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/).

**Reported phenotype names (ClinVar):** Breast-ovarian cancer, familial, susceptibility to, 2, Hereditary cancer-predisposing syndrome, not specified, Fanconi anemia complementation group D1, Hereditary breast ovarian cancer syndrome, Familial cancer of breast, not provided, Hereditary neoplastic syndrome, Tumor predisposition, Neoplastic Syndromes, Hereditary.

## Same-residue context {#hotspot}

Residue **455** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [BRCA2 p.Ser455fs](/variant/brca2-p-ser455fs), [BRCA2 p.Ser455Ter](/variant/brca2-p-ser455ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRCA2 variant pages (same residue, condition, or type): [BRCA2 p.Ser455Ter](/variant/brca2-p-ser455ter), [BRCA2 p.Ser455Pro](/variant/brca2-p-ser455pro), [BRCA2 p.Ser455fs](/variant/brca2-p-ser455fs), [BRCA2 p.Ser455Leu](/variant/brca2-p-ser455leu), [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).

### 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 125943). 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.*