# NM_032043.3(BRIP1):c.2469G>T (p.Arg823Ser)

https://sugi.bio/variant/brip1-p-arg823ser

## Summary

**BRIP1 p.Arg823Ser (c.2469G>T)** is classified **Uncertain significance** in BRIP1 (ClinVar, Multiple submitters, 16 submitters; last evaluated 2026-02-02). AlphaMissense: likely pathogenic (0.9979); Very rare (popmax 0.00102%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs587780239 · 16 submitters · 5 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00102%, nfe)

## For patients & families {#patients}

This is a change in the BRIP1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, submitted by 16 submitters, and is linked to hereditary neoplastic 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.*

|  |  |
| --- | --- |
| Clinical trials | 31 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0019921/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [BRIP1](https://sugi.bio/atlas/gene/BRIP1/) |
| Protein change (HGVS p.) | p.Arg823Ser |
| Coding change (HGVS c.) | c.2469G>T |
| MANE Select transcript | [NM_032043](https://www.ncbi.nlm.nih.gov/nuccore/NM_032043) |
| dbSNP | [rs587780239](https://www.ncbi.nlm.nih.gov/snp/rs587780239/) |
| Variant type | single nucleotide variant |
| Location | chr17:61715974-61715974 (GRCh38) |
| ClinVar | [VCV128173](https://www.ncbi.nlm.nih.gov/clinvar/variation/128173/) |

**All HGVS expressions:** `LRG_300:g.152586G>T`, `LRG_300t1:c.2469G>T`, `NC_000017.10:g.59793335C>A`, `NC_000017.11:g.61715974C>A`, `NG_007409.2:g.152586G>T`, `NM_032043.3:c.2469G>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** (0.9979)
- REVEL 0.869 (moderately pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -15.774 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 4.038, GERP 2.31, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 1%** most-pathogenic-predicted substitutions in BRIP1 (of 7,325 modeled).
- CADD: **PHRED 25.7**. 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 0.84** across the covering region of the MANE Select transcript (61,683,299–61,793,638), spanning 110,339 bp. Chi-square p 3.3e-06. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **below the reporting threshold**. This position is scored for a different substitution (C>G, Δ0.20 donor gain), so this allele was evaluated and its deltas all fell under Δ0.2 — a prediction of no splicing effect for this allele, not a gap in our data. *No ACMG code assigned.*
- Population frequency (gnomAD v4.1): grpmax **0.00102%** (nfe) · FAF95 0.000545% · FAF99 0.00043% · 12/1,174,426 in the highest group · 53/1,605,648 alleles overall — very rare (popmax 0.00102%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Ashkenazi Jewish (not grpmax-eligible) | 0.122% | 819 |
| Remaining individuals (not grpmax-eligible) | 0.00805% | 12,419 |
| European (non-Finnish) (grpmax) | 0.00102% | 97,868 |

Ashkenazi Jewish shows a higher raw frequency than the grpmax group. gnomAD excludes bottlenecked groups — Finnish, Ashkenazi Jewish, Amish and "Remaining individuals" — from grpmax, because founder effects make their frequencies unrepresentative for filtering. The table is sorted by frequency, so an excluded group can sit above the grpmax row.

*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}

**BRIP1** population constraint: LOEUF 0.848, pLI 8.7115e-19, missense-Z 2.4664; 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 J** — Definitive (AR)
- **hereditary breast carcinoma** — Refuted (AD)
- **familial ovarian cancer** — Definitive (AD)

## Protein context {#protein}


AlphaFold model confidence (whole protein): pLDDT 64.19, 35% of residues very-high.

**6 experimental structure(s)** (PDB): [1T15](https://www.rcsb.org/structure/1T15), [1T29](https://www.rcsb.org/structure/1T29), [3AL3](https://www.rcsb.org/structure/3AL3), [9EJ9](https://www.rcsb.org/structure/9EJ9), [9EJA](https://www.rcsb.org/structure/9EJA), [9EJB](https://www.rcsb.org/structure/9EJB).

## What this gene does {#gene-function}

*Describes the biological roles of BRIP1 (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:** BRIP1's established molecular role includes 5'-3' DNA helicase activity. In Reactome, BRIP1 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):** BRIP1 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}

BRIP1 participates in **15 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 |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | curated |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | curated |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | 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 |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | curated |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | 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 |
| [Cytosolic iron-sulfur cluster assembly](https://reactome.org/content/detail/R-HSA-2564830) | electronic |

### Molecular function & processes (GO — experimentally supported) {#go}

**Molecular function:** 5'-3' DNA helicase activity, G-quadruplex unwinding activity.

**Biological process:** regulation of transcription by RNA polymerase II, protein-DNA covalent cross-linking repair.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-02-02.

**Submitter consensus:** conflicting (14 Uncertain significance, 1 Likely benign, 1 not provided).

**Submission history:** 16 submissions (2016–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Sema4, Sema4 | Uncertain significance | criteria provided, single submitter | curation | 2021-05-06 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-25 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-01-04 |
| True Health Diagnostics | Likely benign | no assertion criteria provided | clinical testing | 2017-06-23 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Uncertain significance | no assertion criteria provided | clinical testing |  |
| Fulgent Genetics, Fulgent Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-05-04 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-03-04 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-08-12 |
| GenomeConnect - Invitae Patient Insights Network | not provided | no classification provided | phenotyping only |  |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-10 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2017-06-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-02-02 |
| Dasa | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-30 |
| Blueprint Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-12-07 |
| Myriad Genetics, Inc. | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-02 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-01-13 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [breast cancer](https://sugi.bio/atlas/disease/breast-cancer/), [ovarian cancer](https://sugi.bio/atlas/disease/ovarian-cancer/), [Fanconi anemia complementation group J](https://sugi.bio/atlas/disease/fanconi-anemia-complementation-group-j/), [hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Familial cancer of breast, Fanconi anemia complementation group J, not provided, Malignant tumor of breast, Ovarian cancer, OVARIAN CANCER, SOMATIC, BRIP1-Related Fanconi Anemia, Hereditary neoplastic syndrome, Tumor predisposition.

## Same-residue context {#hotspot}

Residue **823** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BRIP1 p.Arg823fs](/variant/brip1-p-arg823fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRIP1 variant pages (same residue, condition, or type): [BRIP1 p.Arg823Gly](/variant/brip1-p-arg823gly), [BRIP1 p.Arg823Lys](/variant/brip1-p-arg823lys), [BRIP1 p.Arg823Met](/variant/brip1-p-arg823met), [BRIP1 p.Arg823=](/variant/brip1-p-arg823), [BRIP1 p.Arg823fs](/variant/brip1-p-arg823fs), [BRIP1 c.1140+1G>A](/variant/brip1-c-1140-plus-1g-a), [BRIP1 c.1141-2A>C](/variant/brip1-c-1141-minus-2a-c), [BRIP1 c.1141-2A>G](/variant/brip1-c-1141-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 128173). 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.*