# NM_032043.3(BRIP1):c.1207C>T (p.Arg403Trp)

https://sugi.bio/variant/brip1-p-arg403trp

## Summary

**BRIP1 p.Arg403Trp (c.1207C>T)** is classified **Uncertain significance** in BRIP1 (ClinVar, Multiple submitters, 12 submitters; last evaluated 2025-10-29). AlphaMissense: likely pathogenic (0.8243); Very rare (popmax 0.00441%, nfe); Associated with familial ovarian cancer.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs369631413 · 12 submitters · 5 linked conditions · AlphaMissense likely pathogenic · very rare (popmax 0.00441%, 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 12 submitters, and is linked to familial ovarian cancer.

*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 | 1 registered for this condition — see ClinicalTrials.gov |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0020467/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.Arg403Trp |
| Coding change (HGVS c.) | c.1207C>T |
| MANE Select transcript | [NM_032043](https://www.ncbi.nlm.nih.gov/nuccore/NM_032043) |
| dbSNP | [rs369631413](https://www.ncbi.nlm.nih.gov/snp/rs369631413/) |
| Variant type | single nucleotide variant |
| Location | chr17:61799233-61799233 (GRCh38) |
| ClinVar | [VCV136141](https://www.ncbi.nlm.nih.gov/clinvar/variation/136141/) |

**All HGVS expressions:** `LRG_300:g.69327C>T`, `LRG_300t1:c.1207C>T`, `NC_000017.10:g.59876594G>A`, `NC_000017.11:g.61799233G>A`, `NG_007409.2:g.69327C>T`, `NM_032043.3:c.1207C>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** (0.8243)
- REVEL 0.77 (pathogenic-leaning) — agrees with AlphaMissense
- SaProt LLR -17.067 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this damaging
- Conservation: phyloP 8.562, GERP 0.513, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 32.0**. 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.*
- Regional missense constraint: **o/e 0.92** across the covering region of the MANE Select transcript (61,793,692–61,861,539), spanning 67,847 bp. Chi-square p 0.065. 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 **0.00441%** (nfe) · FAF95 0.00342% · FAF99 0.0031% · 52/1,179,634 in the highest group · 57/1,613,330 alleles overall — very rare (popmax 0.00441%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| European (non-Finnish) (grpmax) | 0.00441% | 22,685 |
| African / African-American | 0.00267% | 37,423 |
| Admixed American | 0.00167% | 59,884 |
| Finnish (not grpmax-eligible) | 0.00156% | 63,970 |
| South Asian | 0.0011% | 91,062 |

*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}

Residue **403** lies in the helicase atp-binding domain.

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. p.Arg403Trp falls in the helicase atp-binding domain. 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 2025-10-29.

**Submitter consensus:** unanimous (13/13 Uncertain significance).

**Submission history:** 13 submissions (2016–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Uncertain significance | criteria provided, single submitter | clinical testing | 2017-08-09 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-02-16 |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-30 |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-06-18 |
| Baylor Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-02-29 |
| Myriad Genetics, Inc. | Uncertain significance | criteria provided, single submitter | clinical testing | 2023-03-01 |
| Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-10-15 |
| Counsyl | Uncertain significance | no assertion criteria provided | clinical testing | 2016-08-09 |
| Color Diagnostics, LLC DBA Color Health | Uncertain significance | criteria provided, single submitter | clinical testing | 2024-07-01 |
| Molecular Pathology, Peter Maccallum Cancer Centre | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-03-13 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-10-29 |
| Sema4, Sema4 | Uncertain significance | criteria provided, single submitter | curation | 2022-02-05 |

## Associated conditions {#conditions}

[familial ovarian cancer](https://sugi.bio/atlas/disease/familial-ovarian-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 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):** Familial ovarian cancer, Familial cancer of breast, Fanconi anemia complementation group J, Hereditary cancer-predisposing syndrome, not provided, not specified, Ovarian cancer, Tumor predisposition, Hereditary neoplastic syndrome, Neoplastic Syndromes, Hereditary.

## Same-residue context {#hotspot}

Residue **403** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BRIP1 p.Arg403fs](/variant/brip1-p-arg403fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRIP1 variant pages (same residue, condition, or type): [BRIP1 p.Arg403Gln](/variant/brip1-p-arg403gln), [BRIP1 p.Arg403Gly](/variant/brip1-p-arg403gly), [BRIP1 p.Arg403=](/variant/brip1-p-arg403), [BRIP1 p.Arg403Pro](/variant/brip1-p-arg403pro), [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), [BRIP1 c.1141-2A>T](/variant/brip1-c-1141-minus-2a-t).

### 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 136141). 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.*