# NM_000465.4(BARD1):c.155G>C (p.Arg52Pro)

https://sugi.bio/variant/bard1-p-arg52pro

## Summary

**BARD1 p.Arg52Pro (c.155G>C)** is classified **Uncertain significance** in BARD1 (ClinVar, Multiple submitters, 2 submitters; last evaluated 2025-07-22). AlphaMissense: likely pathogenic (0.8231); Absent from gnomAD v4.1; Associated with hereditary breast carcinoma.

**At a glance:** Uncertain significance · review: Multiple submitters · rsID rs574257684 · 2 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the BARD1 gene that is currently of uncertain significance — a definitive interpretation has not yet been established, 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 | BARD1 is a diagnostic-grade gene on 2 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 | [BARD1](https://sugi.bio/atlas/gene/BARD1/) |
| Protein change (HGVS p.) | p.Arg52Pro |
| Coding change (HGVS c.) | c.155G>C |
| MANE Select transcript | [NM_000465](https://www.ncbi.nlm.nih.gov/nuccore/NM_000465) |
| dbSNP | [rs574257684](https://www.ncbi.nlm.nih.gov/snp/rs574257684/) |
| Variant type | single nucleotide variant |
| Location | chr2:214809415-214809415 (GRCh38) |
| ClinVar | [VCV479166](https://www.ncbi.nlm.nih.gov/clinvar/variation/479166/) |

**All HGVS expressions:** `LRG_297:g.5297G>C`, `LRG_297t1:c.155G>C`, `NC_000002.11:g.215674139C>G`, `NC_000002.12:g.214809415C>G`, `NG_012047.3:g.5297G>C`, `NM_000465.4:c.155G>C`, `NM_001282543.2:c.155G>C`, `NM_001282545.2:c.155G>C`, `NM_001282548.2:c.155G>C`, `NM_001282549.2:c.155G>C`, `NR_104212.2:n.269G>C`, `NR_104215.2:n.269G>C`, `NR_104216.2:n.269G>C`

## Computational & population evidence {#evidence}

**Concordance:** ClinVar classifies this **uncertain**; the computational predictors unanimously lean **damaging** — a triage signal, not a reclassification.

- AlphaMissense **likely pathogenic** (0.8231)
- REVEL 0.623 (indeterminate)
- SaProt LLR -12.519 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt both call this damaging; REVEL makes no call
- SpliceAI predicts **donor loss** (Δ 0.28) — a splice-altering prediction on an uncertain variant — a signal for review
- Conservation: phyloP 7.317, GERP 0.85, phastCons 1 — highly conserved (agrees)
- AlphaMissense ranks this among the **top 10%** most-pathogenic-predicted substitutions in BARD1 (of 4,555 modeled).
- CADD: **PHRED 27.8**. 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 1.06** across the covering region of the MANE Select transcript (214,728,679–214,809,569), spanning 80,890 bp. Chi-square p 0.077. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI deltas (raw): acceptor loss **0.00**, donor loss **0.28**, acceptor gain **0.00**, donor gain **0.01**. Largest is donor loss, 1 bp away.
- SpliceAI deltas (masked): acceptor loss **0.00**, donor loss **0.00**, acceptor gain **0.00**, donor gain **0.01**.
  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}

**BARD1** population constraint: LOEUF 1.087, pLI 1.1813e-19, missense-Z -0.16636; 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):

- **familial ovarian cancer** — Disputed (AD)
- **BARD1-related cancer predisposition** — Definitive (AD)

## Protein context {#protein}

Residue **52** lies in a turn; the 'interaction with brca1' region.

AlphaFold model confidence (whole protein): pLDDT 64.82, 28% of residues very-high.

**11 experimental structure(s)** (PDB): [1JM7](https://www.rcsb.org/structure/1JM7), [2NTE](https://www.rcsb.org/structure/2NTE), [2R1Z](https://www.rcsb.org/structure/2R1Z), [3C5R](https://www.rcsb.org/structure/3C5R), [3FA2](https://www.rcsb.org/structure/3FA2), [6M14](https://www.rcsb.org/structure/6M14) — incl. mutant structure 6M14.

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

*Describes the biological roles of BARD1 (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:** BARD1's established molecular role includes RNA binding. p.Arg52Pro falls in the interaction with brca1 region. In Reactome, BARD1 is annotated in disease pathway(s) including **Defective DNA double strand break response due to BARD1 loss of function**, **Defective DNA double strand break response due to BRCA1 loss of function**.

**Disease mechanism (Reactome):** BARD1 loss or alteration is curated in [Defective DNA double strand break response due to BARD1 loss of function](https://reactome.org/content/detail/R-HSA-9699150), [Defective DNA double strand break response due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9663199), [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331).

### Pathways affected {#pathways}

BARD1 participates in **21 Reactome pathways** (⚕ = disease pathway):

| Pathway (Reactome) | Evidence |
| --- | --- |
| ⚕ [Defective DNA double strand break response due to BARD1 loss of function](https://reactome.org/content/detail/R-HSA-9699150) | other |
| ⚕ [Defective DNA double strand break response due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9663199) | other |
| ⚕ [Defective HDR through Homologous Recombination Repair (HRR) due to PALB2 loss of BRCA1 binding function](https://reactome.org/content/detail/R-HSA-9704331) | other |
| ⚕ [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) | other |
| ⚕ [Defective homologous recombination repair (HRR) due to BRCA1 loss of function](https://reactome.org/content/detail/R-HSA-9701192) | other |
| ⚕ [Impaired BRCA2 binding to PALB2](https://reactome.org/content/detail/R-HSA-9709603) | other |
| ⚕ [Impaired BRCA2 binding to RAD51](https://reactome.org/content/detail/R-HSA-9709570) | other |
| [Negative Regulation of DNA Double Strand Break Response](https://reactome.org/content/detail/R-HSA-9974237) | curated |
| [G2/M DNA damage checkpoint](https://reactome.org/content/detail/R-HSA-69473) | other |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | other |
| [HDR through Single Strand Annealing (SSA)](https://reactome.org/content/detail/R-HSA-5685938) | other |
| [Homologous DNA Pairing and Strand Exchange](https://reactome.org/content/detail/R-HSA-5693579) | other |
| [Metalloprotease DUBs](https://reactome.org/content/detail/R-HSA-5689901) | other |
| [Nonhomologous End-Joining (NHEJ)](https://reactome.org/content/detail/R-HSA-5693571) | other |
| [Presynaptic phase of homologous DNA pairing and strand exchange](https://reactome.org/content/detail/R-HSA-5693616) | other |
| [Processing of DNA double-strand break ends](https://reactome.org/content/detail/R-HSA-5693607) | other |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | other |
| [Regulation of TP53 Activity through Phosphorylation](https://reactome.org/content/detail/R-HSA-6804756) | other |
| [Resolution of D-loop Structures through Holliday Junction Intermediates](https://reactome.org/content/detail/R-HSA-5693568) | other |
| [Resolution of D-loop Structures through Synthesis-Dependent Strand Annealing (SDSA)](https://reactome.org/content/detail/R-HSA-5693554) | other |
| [UCH proteinases](https://reactome.org/content/detail/R-HSA-5689603) | other |

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

**Molecular function:** RNA binding, protein homodimerization activity, protein heterodimerization activity.

**Biological process:** regulation of phosphorylation, positive regulation of apoptotic process, negative regulation of apoptotic process, negative regulation of protein export from nucleus, cellular response to ionizing radiation, protein K6-linked ubiquitination.

## Clinical significance {#significance}

**Uncertain significance** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2025-07-22.

**Submitter consensus:** unanimous (2/2 Uncertain significance).

**Submission history:** 2 submissions (2016–2025); classifications have been stable.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Ambry Genetics | Uncertain significance | criteria provided, single submitter | clinical testing | 2016-10-26 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-07-22 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Familial cancer of breast, Hereditary cancer-predisposing syndrome, BREAST CANCER, FAMILIAL, hereditary breast carcinoma, Hereditary breast cancer, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Tumor predisposition.

## Similar variants {#similar}

Related BARD1 variant pages (same residue, condition, or type): [BARD1 p.Arg52His](/variant/bard1-p-arg52his), [BARD1 p.Arg52Ser](/variant/bard1-p-arg52ser), [BARD1 p.Arg52Gly](/variant/bard1-p-arg52gly), [BARD1 p.Arg52=](/variant/bard1-p-arg52), [BARD1 p.Arg52Phe](/variant/bard1-p-arg52phe), [BARD1 c.1314+1G>A](/variant/bard1-c-1314-plus-1g-a), [BARD1 c.1314+1G>T](/variant/bard1-c-1314-plus-1g-t), [BARD1 c.1396-1G>A](/variant/bard1-c-1396-minus-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 479166). 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.*