NM_058216.3:c.458G>A (p.Gly153Asp) is a missense variant in RAD51C, a gene associated with autosomal dominant predisposition to breast and ovarian cancer (MONDO:0016248, MONDO:0016419) and autosomal recessive Fanconi anemia (MONDO:0019391).1 The ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel specifications for RAD51C v1.0.0 provide no criteria-level modifications (criteria set is empty); generic ACMG/AMP 2015 criteria (PMID:25741868) were applied.2 This variant is extremely rare in population databases: gnomAD v2.1 allele frequency 7.95e-6 (2/251,462 alleles), gnomAD v4.1 allele frequency 1.86e-6 (3/1,614,194 alleles), meeting PM2 at supporting strength.3 In silico predictions are conflicting: REVEL score 0.635 (damaging-leaning) versus BayesDel score 0.233 (benign-leaning); SpliceAI predicts no splice impact (max delta 0.03). Neither PP3 nor BP4 is met.4 ClinVar reports this variant as Uncertain significance by 7 clinical laboratories and Likely pathogenic by 3 laboratories (VariationID 185444); no expert panel consensus exists. PP5 and BP6 are not met.5 Functional studies of RAD51C missense variants have been published (PMID:36099300, PMID:37253112, PMID:39299233), including saturation genome editing covering >99.5% of coding SNVs (PMID:39299233). However, NM_058216.3:c.458G>A (p.Gly153Asp) is not explicitly mentioned in available abstracts and full-text files were not available for verification. PS3 and BS3 remain not assessed pending full-text review. No de novo reports, no segregation data, no case-control enrichment data, and no same-residue pathogenic comparator exist. All remaining assessed criteria (PS1, PS2, PS4, PM5, PM6, PP1, PP4, BS1, BS2, BS4, BP2, BP5) are not met. With only PM2 (supporting) met and no benign criteria satisfied, this variant is classified as a Variant of Uncertain Significance (VUS) under the ACMG/AMP 2015 framework. Definitive classification requires full-text functional data from PMID:39299233 (saturation genome editing) and/or PMID:37253112 (functional characterization of RAD51C missense VUS).
RAD51C
Final classification
VUS
RAD51C c.458G>A · p.Gly153Asp
RAD51C
NM_058216.3:c.458G>A (p.Gly153Asp) is a missense variant in RAD51C, a gene associated with autosomal dominant predisposition to breast and ovarian cancer (MONDO:0016248, MONDO:0016419) and autosomal recessive Fanconi anemia (MONDO:0019391).
ClinGen Hereditary Breast, Ovarian and Pancreatic Cancer Expert Panel Specifications to the ACMG/AMP Variant Interpretation Guidelines for RAD51C Version 1.0.0 v1.0.0 lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting; combination = 1 supporting, which maps to VUS.
Classification rationale
PM2
VUS
RAD51C c.458G>A
PM2
→
VUS
Gene diagram
· NM_058216.3 · variants mapped to exon structure
RAD51C
NM_058216.3
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 21 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_058216.3:c.458G>A is extremely rare in population databases: gnomAD v2.1 allele frequency 7.95e-6 (2/251,462 alleles), gnomAD v4.1 allele frequency 1.86e-6 (3/1,614,194 alleles), both well below the 0.1% PM2 threshold. Zero homozygotes observed. Absent from gnomAD-Canada v1.0.
gnomAD v2.1: AF 7.95e-62/251462 alleles
Assessed · not applied
Pathogenic
PS1
No evidence of a different nucleotide change at codon 153 resulting in the same amino acid substitution (p.Gly153Asp) that has been previously classified as pathogenic.
PS2
No de novo occurrence of NM_058216.3:c.458G>A has been reported in any database or publication reviewed.
PS3
Functional studies of RAD51C missense variants exist (PMID:36099300, PMID:37253112, PMID:39299233) and the saturation genome editing study (PMID:39299233) tested >99.5% of all coding SNVs and would include p.Gly153Asp by design, but NM_058216.3:c.458G>A (p.Gly153Asp) is not explicitly mentioned in any available abstract, and full-text files are unavailable to verify the variant-specific functional result.
PS4
No case-control study demonstrating statistically significant enrichment of NM_058216.3:c.458G>A in affected individuals versus controls has been identified.
PM1
p.Gly153Asp lies within the Rad51/RecA domain (residues ~30-300), but the ClinGen HBOP VCEP for RAD51C v1.0.0 provides no PM1 specification (criteria.json is empty).
PM5
No pathogenic missense variant at the same amino acid residue (Gly153) has been identified as a comparator.
PM6
No de novo observation of NM_058216.3:c.458G>A (assumed or confirmed) has been reported.
PP1
No cosegregation data are available for NM_058216.3:c.458G>A with breast or ovarian cancer in multiple affected family members.
PP2
PP2 requires a low rate of benign missense variation in the gene and that missense variants are a common disease mechanism.
PP3
In silico predictions are conflicting: REVEL score 0.635 (damaging-leaning, >0.5 threshold) but BayesDel score 0.233 (benign-leaning, <0.27 threshold).
PP4
No patient phenotype or family history data specific to NM_058216.3:c.458G>A are available to assess whether the clinical presentation is highly specific for RAD51C-related disease.
PP5
ClinVar reports NM_058216.3:c.458G>A as Uncertain significance by 7 clinical laboratories and Likely pathogenic by 3 laboratories.
Benign
BA1
Allele frequency in gnomAD v2.1 (7.95e-6) and v4.1 (1.86e-6) is far below the BA1 threshold of >1%.
BS1
Allele frequency in gnomAD v2.1 (7.95e-6, 0.0008%) and v4.1 (1.86e-6, 0.00019%) is far below the BS1 threshold of >0.3%.
BS2
NM_058216.3:c.458G>A has not been observed in a homozygous state in gnomAD (0 homozygotes in v2.1 and v4.1) and no compound heterozygous observations in healthy adults have been reported.
BS3
Functional studies exist (PMID:36099300, PMID:37253112, PMID:39299233) but NM_058216.3:c.458G>A (p.Gly153Asp) is not explicitly mentioned in any available abstract, and full-text files are unavailable.
BS4
No family segregation data are available.
BP2
No evidence that NM_058216.3:c.458G>A has been observed in trans with a known pathogenic RAD51C variant in a case of Fanconi anemia or other recessive disorder.
BP4
In silico predictions are conflicting: BayesDel score 0.233 (benign-leaning, <0.27 threshold) suggests no impact, but REVEL score 0.635 (damaging-leaning, >0.5 threshold) contradicts.
BP5
No evidence that NM_058216.3:c.458G>A has been observed in a case with an alternate molecular basis for disease that would refute its pathogenicity.
BP6
ClinVar does not report NM_058216.3:c.458G>A as benign.
N/A · 4
PVS1 · BP1 · BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 1.85851e-06; MAF= 0.00019%, 3/1614194 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 1.66622e-05; MAF= 0.00167%, 1/60016 alleles, homozygotes = 0).
v2.1
This variant is present in gnomAD v2.1 (AF= 7.95349e-06; MAF= 0.00080%, 2/251462 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 2.89084e-05; MAF= 0.00289%, 1/34592 alleles, homozygotes = 0).
🇨🇦 CA
This variant is absent from gnomAD-Canada.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00019%
· 3 / 1,614,194
0 hom
0 hom
Admixed American 1 / 60,016 |
0.0017% |
Remaining individuals 1 / 62,510 |
0.0016% |
European (non-Finnish) 1 / 1,180,028 |
8.5e-05% |
+ 7 not observed (European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0008%
· 2 / 251,462
0 hom
0 hom
Admixed American 1 / 34,592 |
0.0029% |
European (non-Finnish) 1 / 113,750 |
0.00088% |
+ 6 not observed (African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian)
gnomAD Canada 🇨🇦
Absent
· 0 / ?
0 hom
0 hom
Not observed in any ancestry group.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (7 clinical laboratories) and as Likely pathogenic (3 clinical laboratories). (ClinVarID = 185444)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.635. BayesDel score = 0.233494.
Functional
Unknown Oncogenic Effect
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RAD51C, a DNA repair protein, is altered by mutation or deletion in certain breast cancers.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 9 PMIDs not cited in assessment
21980511 ↗
RAD51C germline mutations in breast and ovarian cancer cases from high-risk families.
CLINVAR
23918944 ↗
Tamoxifen and risk of contralateral breast cancer for BRCA1 and BRCA2 mutation carriers.
CLINVAR
25741868 ↗
Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.
CLINVAR
36099300 ↗
Homologous recombination-deficient mutation cluster in tumor suppressor RAD51C identified by comprehensive analysis of cancer variants.
CLINVAR
37253112 ↗
Functional and Clinical Characterization of Variants of Uncertain Significance Identifies a Hotspot for Inactivating Missense Variants in RAD51C.
CLINVAR
12692171 ↗
American Society of Clinical Oncology policy statement update: genetic testing for cancer susceptibility.
CLINVAR
28492532 ↗
Sherloc: a comprehensive refinement of the ACMG-AMP variant classification criteria.
CLINVAR