# NM_058216.3(RAD51C):c.50T>C (p.Phe17Ser)

https://sugi.bio/variant/rad51c-p-phe17ser

## Summary

**RAD51C p.Phe17Ser (c.50T>C)** is classified **Conflicting classifications of pathogenicity** in RAD51C (ClinVar, Conflicting submitters, 4 submitters; last evaluated 2026-04-24). AlphaMissense: likely pathogenic (0.6085); Absent from gnomAD v4.1; Associated with hereditary neoplastic syndrome.

**At a glance:** Conflicting classifications of pathogenicity · review: Conflicting submitters · rsID rs1411454855 · 4 submitters · 2 linked conditions · AlphaMissense likely pathogenic · absent from gnomAD v4.1

## For patients & families {#patients}

This is a change in the RAD51C gene that is of uncertain or conflicting significance (submitters disagree on it), submitted by 4 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 | [RAD51C](https://sugi.bio/atlas/gene/RAD51C/) |
| Protein change (HGVS p.) | p.Phe17Ser |
| Coding change (HGVS c.) | c.50T>C |
| MANE Select transcript | [NM_058216](https://www.ncbi.nlm.nih.gov/nuccore/NM_058216) |
| dbSNP | [rs1411454855](https://www.ncbi.nlm.nih.gov/snp/rs1411454855/) |
| Variant type | single nucleotide variant |
| Location | chr17:58692693-58692693 (GRCh38) |
| ClinVar | [VCV632964](https://www.ncbi.nlm.nih.gov/clinvar/variation/632964/) |

**All HGVS expressions:** `LRG_314:g.5092T>C`, `LRG_314t1:c.50T>C`, `NC_000017.10:g.56770054T>C`, `NC_000017.11:g.58692693T>C`, `NG_023199.1:g.5092T>C`, `NG_047169.1:g.4387A>G`, `NM_002876.4:c.50T>C`, `NM_058216.3:c.50T>C`, `NR_103872.2:n.92T>C`

## Computational & population evidence {#evidence}

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

- AlphaMissense **likely pathogenic** (0.6085)
- REVEL 0.123 (moderately benign-leaning) — differs from AlphaMissense
- SaProt LLR -12.884 (damaging) — agrees with AlphaMissense
- → **In-silico consensus:** AlphaMissense and SaProt call this damaging; REVEL does not
- Conservation: phyloP 5.086, GERP 2.07, phastCons 1 — highly conserved (agrees)
- CADD: **PHRED 22.5**. 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 1.05** across the covering region of the MANE Select transcript (58,692,644–58,734,219), spanning 41,575 bp. Chi-square p 0.31. Describes the region, not this allele; gnomAD v4.1.1's own constrained determination. *Descriptive; no ACMG code applied.*
- SpliceAI: **no splice effect predicted**. SpliceAI outputs four numbers per variant, not one: acceptor loss, donor loss, acceptor gain, donor gain (DS_AL / DS_DL / DS_AG / DS_DG). A loss score is an existing splice site weakened or destroyed; a gain score is a new site created or an existing one strengthened. The release publishes its own filter rule, which we read from the dataset rather than assume: an allele is reported only if the largest of its four deltas reaches 0.2. No allele at this position is in the release, so all four are under 0.2 for every alternate allele here. No figure is shown because none was read: the bound is deduced from that absence. It is a result, not a gap in our data, because the release scores every possible substitution across the transcripts it covers (Ensembl MANE v1.4) before it filters, so what survives for a gene is one continuous stretch. What is measured is that this position sits inside the stretch covered for RAD51C (834 scored positions, the nearest 2 bases away); what is taken from the release's own description, rather than measured, is that coverage inside that stretch is continuous. On that, SpliceAI did score it. *ClinGen's SVI treats the largest of the four as evidence against a splicing effect at or below 0.1, where it may support BP4, and as uninformative between 0.1 and 0.2. We cannot tell which applies here, so these SpliceAI data support neither BP4 nor PP3; that is a statement about this evidence alone, not about the variant's other evidence.*
- 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}

**RAD51C** population constraint: LOEUF 1.139, pLI 3.0641e-13, missense-Z 0.026151; ClinGen dosage — haploinsufficiency 3/3, 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):

- **RAD51C-related cancer predisposition** — Definitive (AD)
- **Fanconi anemia complementation group O** — Limited (AR)

## Protein context {#protein}

Residue **17** lies in the 'required for holliday junction resolution activity' region.

AlphaFold model confidence (whole protein): pLDDT 84.23, 61% of residues very-high.

**17 experimental structure(s)** (PDB): [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), [9OMY](https://www.rcsb.org/structure/9OMY), [9OMZ](https://www.rcsb.org/structure/9OMZ).

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

*Describes the biological roles of RAD51C (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:** p.Phe17Ser falls in the required for holliday junction resolution activity region. In Reactome, RAD51C 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):** RAD51C 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}

RAD51C participates in **11 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 |
| [Factors involved in megakaryocyte development and platelet production](https://reactome.org/content/detail/R-HSA-983231) | 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 |
| [Meiotic recombination](https://reactome.org/content/detail/R-HSA-912446) | electronic |

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

**Biological process:** double-strand break repair via homologous recombination, DNA repair, DNA recombination, positive regulation of G2/M transition of mitotic cell cycle, replication fork processing, supramolecular fiber organization.

## Clinical significance {#significance}

**Conflicting classifications of pathogenicity** — review status Conflicting submitters *(criteria provided, conflicting classifications)*, last evaluated 2026-04-24.

**Submitter consensus:** conflicting (3 Uncertain significance, 1 Benign).

**Submission history:** 4 submissions (2022–2026); classifications have differed over time.

### Submitter classifications {#submitters}

| Submitter | Classification | Review | Method | Date |
| --- | --- | --- | --- | --- |
| GeneDx | Uncertain significance | criteria provided, single submitter | clinical testing | 2022-11-22 |
| Ambry Genetics | Benign | criteria provided, single submitter | clinical testing | 2025-10-28 |
| Labcorp Genetics (formerly Invitae), Labcorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2025-04-07 |
| Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Uncertain significance | criteria provided, single submitter | clinical testing | 2026-04-24 |

## Associated conditions {#conditions}

[hereditary neoplastic syndrome](https://sugi.bio/atlas/disease/hereditary-neoplastic-syndrome/), [Fanconi anemia complementation group O](https://sugi.bio/atlas/disease/fanconi-anemia-complementation-group-o/).

**Reported phenotype names (ClinVar):** Hereditary cancer-predisposing syndrome, not specified, Fanconi anemia complementation group O, not provided, AllHighlyPenetrant, Hereditary Cancer Syndrome, Hereditary neoplastic syndrome, Tumor predisposition, Neoplastic Syndromes, Hereditary, none provided.

## Same-residue context {#hotspot}

Residue **17** carries **1 other pathogenic ClinVar variant** — a recurrently-mutated position: [RAD51C p.Phe17fs](/variant/rad51c-p-phe17fs). *Positional co-occurrence of independent ClinVar records, not functional proof.*

## Similar variants {#similar}

Related RAD51C variant pages (same residue, condition, or type): [RAD51C p.Phe17=](/variant/rad51c-p-phe17), [RAD51C p.Phe17Cys](/variant/rad51c-p-phe17cys), [RAD51C p.Phe17Leu](/variant/rad51c-p-phe17leu), [RAD51C p.Phe17Tyr](/variant/rad51c-p-phe17tyr), [RAD51C p.Phe17fs](/variant/rad51c-p-phe17fs), [RAD51C c.145+1G>A](/variant/rad51c-c-145-plus-1g-a), [RAD51C c.145+1G>T](/variant/rad51c-c-145-plus-1g-t), [RAD51C c.146-1G>A](/variant/rad51c-c-146-minus-1g-a).

### Data sources & attribution {#sources}

ClinVar (NCBI — public domain, built 2026-10-14); gnomAD v4.1 (Broad Institute, built 2026-10-15); 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 632964). 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.*