# NM_002878.4(RAD51D):c.896_*505del597insT (p.Ser299fs)

https://sugi.bio/variant/rad51d-p-ser299fs

## Summary

**RAD51D p.Ser299fs (c.896_*505del597insT)** is classified **Pathogenic** in RAD51D (ClinVar, Single submitter, 2 submitters; last evaluated 2025-08-12). Associated with hereditary breast ovarian cancer syndrome.

**At a glance:** Pathogenic · review: Single submitter · 2 submitters · 2 linked conditions

## For patients & families {#patients}

This is a change in the RAD51D gene that is reported as disease-causing, but on limited review, submitted by 2 submitters, and is linked to hereditary breast ovarian cancer 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.*

|  |  |
| --- | --- |
| Typical inheritance (of this condition) | Autosomal dominant |
| Age of onset (of this condition) | Adult, Elderly |
| Clinical trials | 51 registered for this condition — see ClinicalTrials.gov |
| Diagnostic panels | RAD51D is a diagnostic-grade gene on 6 Genomics England panels |

**Commonly reported features of Hereditary breast and/or ovarian cancer syndrome** (across patients with this condition; presentation varies — frequencies from Orphanet):

- Abnormality of the fallopian tube — Very frequent (99-80%)
- Primary peritoneal carcinoma — Very frequent (99-80%)
- Ovarian neoplasm — Very frequent (99-80%)
- Breast carcinoma — Frequent (79-30%)
- Melanoma — Occasional (29-5%)
- Neoplasm of the pancreas — Occasional (29-5%)
- Prostate cancer — Occasional (29-5%)

**Support & next steps:** [Condition overview & support (NIH GARD)](https://rarediseases.info.nih.gov/diseases/0015010/index) · [Find a genetic counselor (NSGC)](https://findageneticcounselor.nsgc.org/).

## Identity {#identity}

| Field | Value |
| --- | --- |
| Gene | [RAD51D](https://sugi.bio/atlas/gene/RAD51D/) |
| Protein change (HGVS p.) | p.Ser299fs |
| Coding change (HGVS c.) | c.896_*505del597insT |
| MANE Select transcript | [NM_002878](https://www.ncbi.nlm.nih.gov/nuccore/NM_002878) |
| Variant type | Indel |
| Location | chr17:35100448-35101208 (GRCh38) |
| ClinVar | [VCV1713232](https://www.ncbi.nlm.nih.gov/clinvar/variation/1713232/) |

**All HGVS expressions:** `LRG_516:g.23662_24422delinsT`, `LRG_516t1:c.896_*505del597insT`, `NC_000017.10:g.33427467_33428227delinsA`, `NC_000017.11:g.35100448_35101208delinsA`, `NG_031858.1:g.23662_24422delinsT`, `NM_001142571.2:c.956_*505del597insT`, `NM_002878.4:c.896_*505del597insT`, `NM_133629.3:c.560_*505del597insT`, `NR_037711.2:n.922_1518del597insT`, `NR_037712.2:n.787_1383del597insT`

## 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 1.214, GERP 0.245, phastCons 0.283 — 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 the last exon (10 of 10)** — predicted to **escape NMD**, so the truncated protein is likely expressed. An input to PVS1, not an applied code.
- SpliceAI: **not assessed** — the release is built from a substitutions-only source, so it holds no indel 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}

**RAD51D** population constraint: LOEUF 1.092, pLI 1.7901e-11, missense-Z 0.60971; 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):

- **RAD51D-related cancer predisposition** — Definitive (AD)

## Protein context {#protein}

Residue **299** lies in a β-strand.

AlphaFold model confidence (whole protein): pLDDT 88.64, 71% of residues very-high.

**17 experimental structure(s)** (PDB): [2KZ3](https://www.rcsb.org/structure/2KZ3), [8FAZ](https://www.rcsb.org/structure/8FAZ), [8GBJ](https://www.rcsb.org/structure/8GBJ), [8OUY](https://www.rcsb.org/structure/8OUY), [8OUZ](https://www.rcsb.org/structure/8OUZ), [9OMZ](https://www.rcsb.org/structure/9OMZ).

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

*Describes the biological roles of RAD51D (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:** RAD51D's established molecular role includes single-stranded DNA binding. In Reactome, RAD51D 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):** RAD51D 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}

RAD51D participates in **10 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 |
| [HDR through Homologous Recombination (HRR)](https://reactome.org/content/detail/R-HSA-5685942) | 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 |
| [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 |
| [TP53 Regulates Transcription of DNA Repair Genes](https://reactome.org/content/detail/R-HSA-6796648) | curated |

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

**Molecular function:** single-stranded DNA binding, ATP-dependent activity, acting on DNA, gamma-tubulin binding, ATP-dependent DNA damage sensor activity.

**Biological process:** telomere maintenance via recombination, telomere maintenance, double-strand break repair via homologous recombination, DNA strand invasion, supramolecular fiber organization.

## Clinical significance {#significance}

**Pathogenic** — review status Single submitter *(criteria provided, single submitter)*, last evaluated 2025-08-12.

**Submitter consensus:** conflicting (1 Likely pathogenic, 1 Pathogenic).

**Submission history:** 2 submissions (2022–2025); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| BRCAlab, Lund University | Likely pathogenic | no assertion criteria provided | clinical testing | 2022-08-26 |
| German Consortium for Hereditary Breast and Ovarian Cancer, University Hospital Cologne | Pathogenic | criteria provided, single submitter | curation | 2025-08-12 |

## Associated conditions {#conditions}

[hereditary breast ovarian cancer syndrome](https://sugi.bio/atlas/disease/hereditary-breast-ovarian-cancer-syndrome/), [breast-ovarian cancer, familial, susceptibility to, 4](https://sugi.bio/atlas/disease/breast-ovarian-cancer-familial-susceptibility-to-4/).

**Reported phenotype names (ClinVar):** Hereditary breast ovarian cancer syndrome, Breast-ovarian cancer, familial, susceptibility to, 4, Hereditary breast and ovarian cancer syndrome, Hereditary breast and ovarian cancer syndrome (HBOC), Breast and ovarian cancer, Hereditary breast and/or ovarian cancer syndrome, Hereditary breast and ovarian cancer, BRCA1- and BRCA2-Associated Hereditary Breast and Ovarian Cancer.

## Same-residue context {#hotspot}

Residue **299** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [RAD51D p.Ser299_Ter329delinsXaa](/variant/rad51d-p-ser299-ter329delinsxaa). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related RAD51D variant pages (same residue, condition, or type): [RAD51D p.Ser299_Ter329delinsXaa](/variant/rad51d-p-ser299-ter329delinsxaa), [RAD51D p.Gly217_Gln219delinsTer](/variant/rad51d-p-gly217-gln219delinster), [RAD51D p.Leu8fs](/variant/rad51d-p-leu8fs), [RAD51D p.Ser299Phe](/variant/rad51d-p-ser299phe), [RAD51D c.144+1_144+11delinsCC](/variant/rad51d-c-144-plus-1-144-plus-11delinscc), [RAD51D c.346-2delinsCG](/variant/rad51d-c-346-minus-2delinscg), [RAD51D p.Cys9Ter](/variant/rad51d-p-cys9ter), [RAD51D p.Val170fs](/variant/rad51d-p-val170fs).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); 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 1713232). 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.*