# NM_032043.3(BRIP1):c.1661A>G (p.Gln554Arg)

https://sugi.bio/variant/brip1-p-gln554arg

## Summary

**BRIP1 p.Gln554Arg (c.1661A>G)** is classified **Conflicting classifications of pathogenicity** in BRIP1 (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2025-06-29). AlphaMissense: likely benign (0.1056); Very rare (popmax 0.00446%, eas); Associated with hereditary breast carcinoma.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1567813893 · 4 submitters · 3 linked conditions · AlphaMissense likely benign · very rare (popmax 0.00446%, eas)

## 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 4 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.Gln554Arg |
| Coding change (HGVS c.) | c.1661A>G |
| MANE Select transcript | [NM_032043](https://www.ncbi.nlm.nih.gov/nuccore/NM_032043) |
| dbSNP | [rs1567813893](https://www.ncbi.nlm.nih.gov/snp/rs1567813893/) |
| Variant type | single nucleotide variant |
| Location | chr17:61780973-61780973 (GRCh38) |
| ClinVar | [VCV633139](https://www.ncbi.nlm.nih.gov/clinvar/variation/633139/) |

**All HGVS expressions:** `LRG_300:g.87587A>G`, `LRG_300t1:c.1661A>G`, `NC_000017.10:g.59858334T>C`, `NC_000017.11:g.61780973T>C`, `NG_007409.2:g.87587A>G`, `NM_032043.3:c.1661A>G`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1056)
- REVEL 0.1 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -5.054 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP 6.173, GERP 2.1, phastCons 1 — highly conserved (differs from AlphaMissense)
- CADD: **PHRED 21.0**. 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 0.84** 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: **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 **0.00446%** (eas) · FAF95 0.000739% · FAF99 0.000276% · 2/44,868 in the highest group · 3/1,461,762 alleles overall — very rare (popmax 0.00446%, eas).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| East Asian (grpmax) | 0.00446% | 22,434 |
| Remaining individuals (not grpmax-eligible) | 0.0016% | 62,512 |

*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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2025-06-29.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Likely benign).

**Submission history:** 4 submissions (2018–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2018-11-05 |
| Leiden Open Variation Database | Uncertain significance | no assertion criteria provided | curation | 2019-08-13 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-03-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-29 |

## 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, not specified, not provided, Hereditary cancer-predisposing syndrome, Fanconi anemia complementation group J, BREAST CANCER, FAMILIAL, hereditary breast carcinoma, Hereditary breast cancer, BRIP1-Related Fanconi Anemia, AllHighlyPenetrant.

## Same-residue context {#hotspot}

Residue **554** carries **2 other pathogenic ClinVar variants** — a recurrently-mutated position: [BRIP1 p.Gln554fs](/variant/brip1-p-gln554fs), [BRIP1 p.Gln554Ter](/variant/brip1-p-gln554ter). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BRIP1 variant pages (same residue, condition, or type): [BRIP1 p.Gln554Ter](/variant/brip1-p-gln554ter), [BRIP1 p.Gln554Glu](/variant/brip1-p-gln554glu), [BRIP1 p.Gln554His](/variant/brip1-p-gln554his), [BRIP1 p.Gln554Leu](/variant/brip1-p-gln554leu), [BRIP1 p.Gln554=](/variant/brip1-p-gln554), [BRIP1 p.Gln554fs](/variant/brip1-p-gln554fs), [BRIP1 c.1140+1G>A](/variant/brip1-c-1140-plus-1g-a), [BRIP1 c.1141-2A>C](/variant/brip1-c-1141-minus-2a-c).

### 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 633139). 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.*