# NM_000465.4(BARD1):c.33G>T (p.Gln11His)

https://sugi.bio/variant/bard1-p-gln11his

## Summary

**BARD1 p.Gln11His (c.33G>T)** is classified **Conflicting classifications of pathogenicity** in BARD1 (ClinVar, Conflicting submitters, 26 submitters; last evaluated 2026-06-01). AlphaMissense: likely benign (0.1802); Rare (popmax 0.256%, amr); Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs143914387 · 26 submitters · 3 linked conditions · AlphaMissense likely benign · rare (popmax 0.256%, amr)

## For patients & families {#patients}

This is a change in the BARD1 gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 26 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 | [BARD1](https://sugi.bio/atlas/gene/BARD1/) |
| Protein change (HGVS p.) | p.Gln11His |
| Coding change (HGVS c.) | c.33G>T |
| MANE Select transcript | [NM_000465](https://www.ncbi.nlm.nih.gov/nuccore/NM_000465) |
| dbSNP | [rs143914387](https://www.ncbi.nlm.nih.gov/snp/rs143914387/) |
| Variant type | single nucleotide variant |
| Location | chr2:214809537-214809537 (GRCh38) |
| ClinVar | [VCV127737](https://www.ncbi.nlm.nih.gov/clinvar/variation/127737/) |

**All HGVS expressions:** `LRG_297:g.5175G>T`, `LRG_297t1:c.33G>T`, `NC_000002.11:g.215674261C>A`, `NC_000002.12:g.214809537C>A`, `NG_012047.3:g.5175G>T`, `NM_000465.4:c.33G>T`, `NM_001282543.2:c.33G>T`, `NM_001282545.2:c.33G>T`, `NM_001282548.2:c.33G>T`, `NM_001282549.2:c.33G>T`, `NR_104212.2:n.147G>T`, `NR_104215.2:n.147G>T`, `NR_104216.2:n.147G>T`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely benign** (0.1802)
- REVEL 0.156 (moderately benign-leaning) — agrees with AlphaMissense
- SaProt LLR -7.833 (tolerated) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense, REVEL and SaProt all call this tolerated
- Conservation: phyloP -0.12, GERP -1.02 — not a conserved position (phyloP < 0.1, ACGS BP7 cut)
- CADD: **PHRED 14.91**. 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: **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 **0.256%** (amr) · FAF95 0.222% · FAF99 0.209% · 146/57,008 in the highest group · 2,481/1,577,884 alleles overall — rare (popmax 0.256%, amr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| Finnish (not grpmax-eligible) | 0.352% | 284 |
| Admixed American (grpmax) | 0.256% | 390 |
| Amish (not grpmax-eligible) | 0.219% | 456 |
| European (non-Finnish) | 0.168% | 594 |
| Remaining individuals (not grpmax-eligible) | 0.159% | 630 |
| Middle Eastern | 0.134% | 747 |
| Ashkenazi Jewish (not grpmax-eligible) | 0.0827% | 1,210 |
| South Asian | 0.0408% | 2,451 |
| African / African-American | 0.0216% | 4,638 |
| East Asian | 0.00232% | 43,040 |

Finnish 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}

**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 **11** lies in the 'disordered' 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.Gln11His falls in the disordered 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}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-06-01.

**Submitter consensus:** conflicting (18 Likely benign, 7 Benign, 1 Uncertain significance).

**Submission history:** 26 submissions (2015–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2016-05-03 |
| Mendelics | Likely benign | criteria provided, single submitter | clinical testing | 2019-05-28 |
| Sema4, Sema4 | Benign | criteria provided, single submitter | curation | 2021-01-11 |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Benign | criteria provided, single submitter | clinical testing | 2023-07-07 |
| Quest Diagnostics Nichols Institute San Juan Capistrano | Benign | criteria provided, single submitter | clinical testing | 2022-06-22 |
| PreventionGenetics, part of Exact Sciences | Likely benign | criteria provided, single submitter | clinical testing | 2017-01-30 |
| Department of Pathology and Laboratory Medicine, Sinai Health System | Likely benign | no assertion criteria provided | clinical testing |  |
| Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| Genetic Services Laboratory, University of Chicago | Likely benign | criteria provided, single submitter | clinical testing | 2020-02-04 |
| Color Diagnostics, LLC DBA Color Health | Likely benign | criteria provided, single submitter | clinical testing | 2015-02-11 |
| Fulgent Genetics, Fulgent Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2021-08-13 |
| Institute for Clinical Genetics, University Hospital TU Dresden, University Hospital TU Dresden | Likely benign | criteria provided, single submitter | clinical testing | 2021-11-03 |
| CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario | Likely benign | criteria provided, single submitter | clinical testing | 2023-05-01 |
| Ambry Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2018-12-19 |
| Counsyl | Likely benign | no assertion criteria provided | clinical testing | 2016-10-11 |
| Molecular Diagnostics Laboratory, Catalan Institute of Oncology | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-06-04 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-02-04 |
| CeGaT Center for Human Genetics Tuebingen | Likely benign | criteria provided, single submitter | clinical testing | 2026-06-01 |
| Illumina Laboratory Services, Illumina | Likely benign | criteria provided, single submitter | clinical testing | 2018-01-13 |
| Center of Medical Genetics and Primary Health Care | Benign | no assertion criteria provided | clinical testing |  |
| Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) | Likely benign | no assertion criteria provided | clinical testing |  |
| Genome Diagnostics Laboratory, Amsterdam University Medical Center | Likely benign | no assertion criteria provided | clinical testing |  |
| GeneDx | Likely benign | criteria provided, single submitter | clinical testing | 2020-09-26 |
| Myriad Genetics, Inc. | Benign | criteria provided, single submitter | clinical testing | 2025-01-08 |
| Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital | Likely benign | criteria provided, single submitter | clinical testing | 2025-12-29 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-11-26 |

## Associated conditions {#conditions}

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

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, Familial cancer of breast, not specified, not provided, Malignant tumor of breast, Breast and/or ovarian cancer, Hereditary neoplastic syndrome, Tumor predisposition, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome.

## Same-residue context {#hotspot}

Residue **11** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [BARD1 p.Gln11fs](/variant/bard1-p-gln11fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related BARD1 variant pages (same residue, condition, or type): [BARD1 p.Gln11Leu](/variant/bard1-p-gln11leu), [BARD1 p.Gln11Pro](/variant/bard1-p-gln11pro), [BARD1 p.Gln11_Arg15del](/variant/bard1-p-gln11-arg15del), [BARD1 p.Gln11_Arg15dup](/variant/bard1-p-gln11-arg15dup), [BARD1 p.Gln11fs](/variant/bard1-p-gln11fs), [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 127737). 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.*