# NM_000465.4(BARD1):c.896del (p.Thr299fs)

https://sugi.bio/variant/bard1-p-thr299fs

## Summary

**BARD1 p.Thr299fs (c.896del)** is classified **Pathogenic** in BARD1 (ClinVar, Single submitter, 1 submitter; last evaluated 2025-12-03). Associated with hereditary breast carcinoma.

**At a glance:** Pathogenic · review: Single submitter · 1 submitter · 1 linked condition

## For patients & families {#patients}

This is a change in the BARD1 gene that is reported as disease-causing, but on limited review, submitted by 1 submitter, 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.Thr299fs |
| Coding change (HGVS c.) | c.896del |
| MANE Select transcript | [NM_000465](https://www.ncbi.nlm.nih.gov/nuccore/NM_000465) |
| Variant type | Deletion |
| Location | chr2:214780978-214780978 (GRCh38) |
| ClinVar | [VCV4732480](https://www.ncbi.nlm.nih.gov/clinvar/variation/4732480/) |

**All HGVS expressions:** `LRG_297:g.33734del`, `LRG_297t1:c.896del`, `NC_000002.11:g.215645702del`, `NC_000002.12:g.214780978del`, `NG_012047.3:g.33734del`, `NM_000465.4:c.896del`, `NM_001282543.2:c.839del`, `NM_001282545.2:c.215+16083del`, `NM_001282548.2:c.159-28423del`, `NM_001282549.2:c.364+11319del`, `NR_104212.2:n.861del`, `NR_104215.2:n.804del`

## 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 0.862, GERP -1.76, phastCons 0.135 — weakly conserved position
- Molecular consequence: **frameshift** — a predicted loss-of-function variant. ClinGen curates **sufficient evidence for haploinsufficiency** in this gene, supporting a loss-of-function disease mechanism. *Descriptive; not an applied PVS1 code.*
- Nonsense-mediated decay: the premature termination codon is **in exon 4 of 11**, so the transcript is predicted to undergo NMD.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no deletion variants. That is a property of the dataset, not of the variant, and is not evidence against a splicing effect.

*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 **299** lies in a modified residue (phosphothreonine).

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. 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}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-12-03.

**Submitter consensus:** unanimous (1/1 Pathogenic).

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Labcorp Genetics (formerly Invitae), Labcorp | Pathogenic | criteria provided, single submitter | clinical testing | 2025-12-03 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Familial cancer of breast, hereditary breast carcinoma, BREAST CANCER, FAMILIAL, Hereditary breast cancer.

## Similar variants {#similar}

Related BARD1 variant pages (same residue, condition, or type): [BARD1 p.Thr299Ile](/variant/bard1-p-thr299ile), [BARD1 p.Thr299=](/variant/bard1-p-thr299), [BARD1 p.Thr299Ala](/variant/bard1-p-thr299ala), [BARD1 p.Thr299Ser](/variant/bard1-p-thr299ser), [BARD1 c.1306_1314+7del](/variant/bard1-c-1306-1314-plus-7del), [BARD1 c.158+2_158+10del](/variant/bard1-c-158-plus-2-158-plus-10del), [BARD1 c.1676_1677+23del](/variant/bard1-c-1676-1677-plus-23del), [BARD1 c.1678-1_1678del](/variant/bard1-c-1678-minus-1-1678del).

### 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 4732480). 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.*