# NM_032043.3(BRIP1):c.249A>G (p.Gln83=)

https://sugi.bio/variant/brip1-p-gln83

## Summary

**BRIP1 p.Gln83= (c.249A>G)** is classified **Conflicting classifications of pathogenicity** in BRIP1 (ClinVar, Conflicting submitters, 11 submitters; last evaluated 2026-02-03). Ultra-rare (popmax 0.02%, nfe); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs45528833 · 11 submitters · 3 linked conditions · ultra-rare (popmax 0.02%, nfe)

## For patients & families {#patients}

This is a change in the BRIP1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 11 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.Gln83= |
| Coding change (HGVS c.) | c.249A>G |
| MANE Select transcript | [NM_032043](https://www.ncbi.nlm.nih.gov/nuccore/NM_032043) |
| dbSNP | [rs45528833](https://www.ncbi.nlm.nih.gov/snp/rs45528833/) |
| Variant type | single nucleotide variant |
| Location | chr17:61857188-61857188 (GRCh38) |
| ClinVar | [VCV184395](https://www.ncbi.nlm.nih.gov/clinvar/variation/184395/) |

**All HGVS expressions:** `LRG_300:g.11372A>G`, `LRG_300t1:c.249A>G`, `NC_000017.10:g.59934549T>C`, `NC_000017.11:g.61857188T>C`, `NG_007409.2:g.11372A>G`, `NM_032043.3:c.249A>G`

## 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 (below), not from a missing predictor score.
- Conservation: phyloP -2.866, GERP -2.9 — fast-evolving / accelerated position
- CADD: **PHRED 4.829**. 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: **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 **0.02%** (nfe) · FAF95 0.0179% · FAF99 0.0171% · 236/1,179,934 in the highest group · 267/1,614,068 alleles overall — ultra-rare (popmax 0.02%, nfe).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Remaining individuals (not grpmax-eligible) | 0.0304% | 3,290 |
| European (non-Finnish) (grpmax) | 0.02% | 5,000 |
| African / African-American | 0.012% | 8,339 |
| Finnish (not grpmax-eligible) | 0.00469% | 21,343 |

Remaining individuals 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}

Residue **83** 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.Gln83= 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-02-03.

**Submitter consensus:** conflicting (8 Likely benign, 2 Benign, 1 Uncertain significance).

**Submission history:** 11 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2015-03-03 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2014-10-08 |
| Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. | Likely benign | no assertion criteria provided | clinical testing | 2022-01-24 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2024-08-09 |
| ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories | Likely benign | criteria provided, single submitter | clinical testing | 2018-03-17 |
| Sema4, Sema4 | Likely benign | criteria provided, single submitter | curation | 2020-11-30 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2016-09-30 |
| PreventionGenetics, part of Exact Sciences | Likely benign | no assertion criteria provided | clinical testing | 2019-11-19 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | criteria provided, single submitter | clinical testing | 2022-05-30 |
| Labcorp Genetics (formerly Invitae), Labcorp | Likely benign | criteria provided, single submitter | clinical testing | 2026-02-03 |
| Eurofins Ntd Llc (ga) | Uncertain significance | criteria provided, single submitter | clinical testing | 2015-04-09 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [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, not provided, Familial cancer of breast, Fanconi anemia complementation group J, BRIP1-related disorder, BRIP1-related condition, BRIP1-related disorders, Tumor predisposition, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome.

## Same-residue context {#hotspot}

Residue **83** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BRIP1 p.Gln83Ter](/variant/brip1-p-gln83ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRIP1 variant pages (same residue, condition, or type): [BRIP1 p.Gln83Ter](/variant/brip1-p-gln83ter), [BRIP1 p.Gln83Arg](/variant/brip1-p-gln83arg), [BRIP1 p.Gln83His](/variant/brip1-p-gln83his), [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 2026-10-11); 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 184395). 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.*