# NM_005732.4(RAD50):c.2091C>T (p.Val697=)

https://sugi.bio/variant/rad50-p-val697

## Summary

**RAD50 p.Val697= (c.2091C>T)** is classified **Benign/Likely benign** in RAD50 (ClinVar, Multiple submitters, 9 submitters; last evaluated 2026-01-05). Rare (popmax 0.537%, afr); Associated with hereditary neoplastic syndrome.

**At a glance:** Benign/Likely benign · review: Multiple submitters · rsID rs61747588 · 9 submitters · 3 linked conditions · rare (popmax 0.537%, afr)

## For patients & families {#patients}

This is a change in the RAD50 gene that is classified as benign/likely benign — not considered disease-causing, submitted by 9 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 | [RAD50](https://sugi.bio/atlas/gene/RAD50/) |
| Protein change (HGVS p.) | p.Val697= |
| Coding change (HGVS c.) | c.2091C>T |
| MANE Select transcript | [NM_005732](https://www.ncbi.nlm.nih.gov/nuccore/NM_005732) |
| dbSNP | [rs61747588](https://www.ncbi.nlm.nih.gov/snp/rs61747588/) |
| Variant type | single nucleotide variant |
| Location | chr5:132595694-132595694 (GRCh38) |
| ClinVar | [VCV142438](https://www.ncbi.nlm.nih.gov/clinvar/variation/142438/) |

**All HGVS expressions:** `LRG_312:g.43718C>T`, `LRG_312t1:c.2091C>T`, `NC_000005.10:g.132595694C>T`, `NC_000005.9:g.131931386C>T`, `NG_021151.2:g.43718C>T`, `NM_005732.4:c.2091C>T`

## 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 0.928, GERP 2.23, phastCons 1 — weakly conserved position
- CADD: **PHRED 10.0**. 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.*
- 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 **0.537%** (afr) · FAF95 0.494% · FAF99 0.477% · 403/75,002 in the highest group · 459/1,613,774 alleles overall — rare (popmax 0.537%, afr).

| Ancestry group | Allele frequency | 1 in |
| --- | --- | --- |
| African / African-American (grpmax) | 0.537% | 186 |
| Remaining individuals (not grpmax-eligible) | 0.0416% | 2,404 |
| Admixed American | 0.0383% | 2,609 |
| Middle Eastern | 0.033% | 3,030 |
| European (non-Finnish) | 0.000424% | 235,947 |

*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}

**RAD50** population constraint: LOEUF 0.889, pLI 1.1799e-33, missense-Z 2.2921; ClinGen dosage — haploinsufficiency 1/3, triplosensitivity 0/3. *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):

- **hereditary breast carcinoma** — Refuted (AD)
- **familial ovarian cancer** — Refuted (AD)

## Protein context {#protein}

Residue **697** lies in the zinc-hook domain; a UniProt-annotated variant site (in); an α-helix.

AlphaFold model confidence (whole protein): pLDDT 82.83, 14% of residues very-high.

**6 experimental structure(s)** (PDB): [5GOX](https://www.rcsb.org/structure/5GOX), [9Q9H](https://www.rcsb.org/structure/9Q9H), [9Q9I](https://www.rcsb.org/structure/9Q9I), [9Q9J](https://www.rcsb.org/structure/9Q9J), [9Q9K](https://www.rcsb.org/structure/9Q9K), [9Q9M](https://www.rcsb.org/structure/9Q9M).

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

*Describes the biological roles of RAD50 (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:** RAD50's established molecular role includes DNA binding. p.Val697= falls in the zinc-hook domain. In Reactome, RAD50 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):** RAD50 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}

RAD50 participates in **20 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 |
| [DNA Damage/Telomere Stress Induced Senescence](https://reactome.org/content/detail/R-HSA-2559586) | 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 MMEJ (alt-NHEJ)](https://reactome.org/content/detail/R-HSA-5685939) | 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 |
| [Nonhomologous End-Joining (NHEJ)](https://reactome.org/content/detail/R-HSA-5693571) | 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 |
| [Recruitment and ATM-mediated phosphorylation of repair and signaling proteins at DNA double strand breaks](https://reactome.org/content/detail/R-HSA-5693565) | 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 |
| [Sensing of DNA Double Strand Breaks](https://reactome.org/content/detail/R-HSA-5693548) | curated |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | electronic |

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

**Molecular function:** DNA binding, ATP hydrolysis activity, protein-macromolecule adaptor activity, identical protein binding, protein serine/threonine kinase activator activity.

**Biological process:** regulation of mitotic recombination, double-strand break repair via homologous recombination, DNA double-strand break processing, DNA repair, double-strand break repair, DNA recombination.

## Clinical significance {#significance}

**Benign/Likely benign** — review status Multiple submitters *(criteria provided, multiple submitters, no conflicts)*, last evaluated 2026-01-05.

**Submitter consensus:** conflicting (7 Benign, 3 Likely benign).

**Submission history:** 10 submissions (2014–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| Sema4, Sema4 | Benign | criteria provided, single submitter | curation | 2021-09-03 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2014-11-29 |
| GeneDx | Benign | criteria provided, single submitter | clinical testing | 2014-01-23 |
| Labcorp Genetics (formerly Invitae), Labcorp | Benign | criteria provided, single submitter | clinical testing | 2026-01-05 |
| Blueprint Genetics | Likely benign | criteria provided, single submitter | clinical testing | 2024-09-11 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Benign | criteria provided, single submitter | clinical testing | 2018-01-08 |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Benign | criteria provided, single submitter | clinical testing | 2023-07-07 |
| Breakthrough Genomics, Breakthrough Genomics | Likely benign | criteria provided, single submitter | not provided |  |
| KCCC/NGS Laboratory, Kuwait Cancer Control Center | Benign | criteria provided, single submitter | clinical testing | 2025-02-01 |
| Counsyl | Likely benign | no assertion criteria provided | clinical testing | 2016-06-03 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [Nijmegen breakage syndrome-like disorder](https://sugi.bio/atlas/disease/nijmegen-breakage-syndrome-like-disorder/), [hereditary breast carcinoma](https://sugi.bio/atlas/disease/hereditary-breast-carcinoma/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, not specified, Nijmegen breakage syndrome-like disorder, Familial cancer of breast, not provided, Neoplastic Syndromes, Hereditary, Hereditary Cancer Syndrome, Tumor predisposition, Hereditary neoplastic syndrome, AllHighlyPenetrant.

## Similar variants {#similar}

Related RAD50 variant pages (same residue, condition, or type): [RAD50 p.Val697Ile](/variant/rad50-p-val697ile), [RAD50 c.1051+1G>A](/variant/rad50-c-1051-plus-1g-a), [RAD50 c.1052-1G>A](/variant/rad50-c-1052-minus-1g-a), [RAD50 c.1052-1G>T](/variant/rad50-c-1052-minus-1g-t), [RAD50 c.1052-2A>C](/variant/rad50-c-1052-minus-2a-c), [RAD50 c.1245+1G>A](/variant/rad50-c-1245-plus-1g-a), [RAD50 c.129+1G>A](/variant/rad50-c-129-plus-1g-a), [RAD50 c.129+1G>T](/variant/rad50-c-129-plus-1g-t).

### 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 2026-10-14); 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 142438). 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.*