# NM_032043.3(BRIP1):c.3711T>C (p.Ser1237=)

https://sugi.bio/variant/brip1-p-ser1237

## Summary

**BRIP1 p.Ser1237= (c.3711T>C)** is classified **Likely benign** in BRIP1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2019-01-24). Absent from gnomAD v4.1; Associated with hereditary breast carcinoma.

**At a glance:** Likely benign · review: Multiple submitters · rsID rs786203915 · 2 submitters · 3 linked conditions · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BRIP1 gene that is classified as likely benign — not considered disease-causing, submitted by 2 submitters, and is linked to hereditary breast carcinoma.

*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, Multigenic/multifactorial |
| Age of onset (of this condition) | Adult, Elderly |
| Clinical trials | 10 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | BRIP1 is a diagnostic-grade gene on 21 Genomics England panels |

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0017142/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.Ser1237= |
| Coding change (HGVS c.) | c.3711T>C |
| MANE Select transcript | [NM_032043](https://www.ncbi.nlm.nih.gov/nuccore/NM_032043) |
| dbSNP | [rs786203915](https://www.ncbi.nlm.nih.gov/snp/rs786203915/) |
| Variant type | single nucleotide variant |
| Location | chr17:61683335-61683335 (GRCh38) |
| ClinVar | [VCV187678](https://www.ncbi.nlm.nih.gov/clinvar/variation/187678/) |

**All HGVS expressions:** `LRG_300:g.185225T>C`, `LRG_300t1:c.3711T>C`, `NC_000017.10:g.59760696A>G`, `NC_000017.11:g.61683335A>G`, `NG_007409.2:g.185225T>C`, `NM_032043.3:c.3711T>C`

## Computational & population evidence {#evidence}

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

- **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 and, for splice-region changes, SpliceAI (below), not from a missing predictor score.
- SpliceAI predicts **donor loss** (Δ 0.22) — a splice-altering prediction the current classification does not reflect
- Conservation: phyloP 1.462, GERP -2.56, phastCons 0.934 — weakly conserved position
- CADD: **PHRED 2.527**. 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 deltas (raw): acceptor loss **0.00**, donor loss **0.22**, acceptor gain **0.00**, donor gain **0.00**. Largest is donor loss, 16 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.00**.
  Masked SpliceAI — what Ensembl VEP and the Broad lookup serve by default — is below the reporting threshold here, so those tools show **no splice signal** for this allele. Masking zeroes a loss scored against a position that is not an annotated splice site, and a gain that merely strengthens an existing one, so the raw score above is describing a cryptic site rather than the site the variant sits on. *No ACMG code is assigned either way.*
- Population frequency: **absent from gnomAD v4.1** — a rarity signal (ACMG PM2-supporting), not evidence of pathogenicity on its own.

*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 3/3, 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 J** — Definitive (AR)
- **hereditary breast carcinoma** — Refuted (AD)
- **familial ovarian cancer** — Definitive (AD)

## Protein context {#protein}

Residue **1237** lies in a modified residue (phosphoserine).

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}

**Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2019-01-24.

**Submitter consensus:** unanimous (2/2 Likely benign).

**Submission history:** 2 submissions (2014–2019); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2014-12-18 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2019-01-24 |

## Associated conditions {#conditions}

[hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/), [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/).

**Reported phenotype names (ClinVar):** Familial cancer of breast, Hereditary cancer-predisposing syndrome, Fanconi anemia complementation group J, BREAST CANCER, FAMILIAL, Hereditary breast cancer, hereditary breast carcinoma, BRIP1-Related Fanconi Anemia, Hereditary Cancer Syndrome, Neoplastic Syndromes, Hereditary, Tumor predisposition.

## Similar variants {#similar}

Related BRIP1 variant pages (same residue, condition, or type): [BRIP1 p.Ser1237Phe](/variant/brip1-p-ser1237phe), [BRIP1 p.Ser1237Thr](/variant/brip1-p-ser1237thr), [BRIP1 p.Ser1237Tyr](/variant/brip1-p-ser1237tyr), [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), [BRIP1 c.1340+1G>A](/variant/brip1-c-1340-plus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-14); 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 187678). 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.*