# NM_000059.4(BRCA2):c.1123C>T (p.Pro375Ser)

https://sugi.bio/variant/brca2-p-pro375ser

## Summary

**BRCA2 p.Pro375Ser (c.1123C>T)** is classified **Benign** in BRCA2 (ClinVar, Expert panel, 16 submitters; last evaluated 2015-08-10). AlphaMissense: likely benign (0.105); Ultra-rare (popmax 0.0617%, amr); Associated with breast-ovarian cancer, familial, susceptibility to, 2.

**At a glance:** Benign · review: Expert panel · rsID rs80358408 · 16 submitters · 3 linked conditions · AlphaMissense likely benign · ultra-rare (popmax 0.0617%, amr)

## For patients & families {#patients}

This is a change in the BRCA2 gene that is classified as benign — not considered disease-causing, submitted by 16 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.Pro375Ser |
| Coding change (HGVS c.) | c.1123C>T |
| MANE Select transcript | [NM_000059](https://www.ncbi.nlm.nih.gov/nuccore/NM_000059) |
| dbSNP | [rs80358408](https://www.ncbi.nlm.nih.gov/snp/rs80358408/) |
| Variant type | single nucleotide variant |
| Location | chr13:32332601-32332601 (GRCh38) |
| ClinVar | [VCV51066](https://www.ncbi.nlm.nih.gov/clinvar/variation/51066/) |

**All HGVS expressions:** `LRG_293:g.22122C>T`, `LRG_293t1:c.1123C>T`, `NC_000013.10:g.32906738C>T`, `NC_000013.11:g.32332601C>T`, `NG_012772.3:g.22122C>T`, `NM_000059.4:c.1123C>T`, `U43746.1:n.1351C>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.105)
- REVEL 0.211 (benign-leaning) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and REVEL both call this tolerated; SaProt makes no call
- Conservation: phyloP -1.967, GERP -3.71 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- **SaProt:** not scored — SaProt is structure-aware and AlphaFold DB has no model for this protein. That is a property of the dataset, not of the variant, and is not evidence either way.
- CADD: **PHRED 6.897**. 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: **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 33 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 **0.0617%** (amr) · FAF95 0.0459% · FAF99 0.0405% · 37/60,002 in the highest group · 67/1,613,952 alleles overall — ultra-rare (popmax 0.0617%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Admixed American (grpmax) | 0.0617% | 1,622 |
| Remaining individuals (not grpmax-eligible) | 0.0272% | 3,676 |
| African / African-American | 0.004% | 25,007 |
| European (non-Finnish) | 0.000848% | 117,992 |

*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 **375** lies in the 'disordered' 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.Pro375Ser falls in the disordered 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}

**Benign** — review status Expert panel *(reviewed by expert panel)*, last evaluated 2015-08-10.

**Submitter consensus:** conflicting (9 Benign, 6 Likely benign, 1 Uncertain significance).

**Submission history:** 16 submissions (2002–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Mendelics | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2020-08-24 |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-12-16 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| Dasa | Benign | criteria provided, single submitter | clinical testing | 2025-11-27 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-08-12 |
| Breast Cancer Information Core (BIC) (BRCA2) | Uncertain significance | no assertion criteria provided | clinical testing | 2002-05-29 |
| Sharing Clinical Reports Project (SCRP) | Benign | no assertion criteria provided | clinical testing | 2012-05-01 |
| National Health Laboratory Service, Universitas Academic Hospital and University of the Free State | Benign | criteria provided, single submitter | clinical testing | 2022-04-19 |
| Sema4, Sema4 | Benign | criteria provided, single submitter | curation | 2020-12-16 |
| Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Likely benign | criteria provided, single submitter | clinical testing | 2023-04-18 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2014-11-19 |
| Eurofins Ntd Llc (ga) | Likely benign | criteria provided, single submitter | clinical testing | 2015-03-25 |
| Counsyl | Likely benign | no assertion criteria provided | literature only | 2014-07-21 |
| Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) | Benign | reviewed by expert panel | curation | 2015-08-10 |
| Color Diagnostics, LLC DBA Color Health | Benign | criteria provided, single submitter | clinical testing | 2016-08-31 |

## 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 cancer-predisposing syndrome, not specified, Hereditary breast ovarian cancer syndrome, not provided, Tumor predisposition, Neoplastic Syndromes, Hereditary, Hereditary neoplastic syndrome, Hereditary Cancer Syndrome, AllHighlyPenetrant.

## Similar variants {#similar}

Related BRCA2 variant pages (same residue, condition, or type): [BRCA2 p.Pro375=](/variant/brca2-p-pro375), [BRCA2 p.Pro375Arg](/variant/brca2-p-pro375arg), [BRCA2 p.Pro375Leu](/variant/brca2-p-pro375leu), [BRCA2 p.Pro375His](/variant/brca2-p-pro375his), [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 51066). 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.*