NM_002878.4:c.829C>G (p.Leu277Val) is a missense variant in RAD51D, a moderate-penetrance hereditary breast and ovarian cancer predisposition gene involved in homologous recombination repair.1 This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 0.00040% (1/251,446 alleles) and gnomAD v4.1 AF = 0.00037% (6/1,614,064 alleles), meeting PM2 at supporting strength.2 Multiple in silico predictors consistently indicate a tolerated or benign effect: REVEL score 0.131, BayesDel score -0.327, and SpliceAI max delta 0.00. These independent computational lines of evidence support BP4 at supporting strength.3 No functional studies, case-control data, family segregation analysis, de novo reports, or variant-specific publications were identified for this variant. ClinVar reports Uncertain significance (3 clinical laboratories, 1-star review). OncoKB reports unknown oncogenic effect.4 Applying generic ACMG/AMP 2015 combination rules: PM2 (supporting) + BP4 (supporting) yields an overall classification of Uncertain Significance (VUS), consistent with the ClinVar consensus.5
RAD51D
Final classification
VUS
RAD51D c.829C>G · p.Leu277Val
RAD51D
NM_002878.4:c.829C>G (p.Leu277Val) is a missense variant in RAD51D, a moderate-penetrance hereditary breast and ovarian cancer predisposition gene involved in homologous recombination repair.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: PM2 supporting, BP4 supporting; combination = 1 supporting + 1 supporting benign, which maps to VUS.
Classification rationale
PM2
BP4
VUS
RAD51D c.829C>G
PM2 + BP4
→
VUS
Gene diagram
· NM_002878.4 · variants mapped to exon structure
RAD51D
NM_002878.4
Fetching transcript structure from UCSC…
Applied criteria · 2 applied · 21 assessed
Applied · 2
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
supporting
Pathogenic
NM_002878.4:c.829C>G is absent or present at extremely low frequency in population databases. gnomAD v2.1: 1/251,446 alleles (AF = 0.00040%). gnomAD v4.1: 6/1,614,064 alleles (AF = 0.00037%). Both are well below the 0.1% threshold for PM2 application. No homozygotes observed.
gnomAD v2.1: 1/251446 alleles (AF = 3.977e-06)no homozygotes.
✓
BP4
supporting
Benign
Multiple independent lines of computational evidence suggest this variant has no deleterious impact on the gene product. REVEL score 0.131 (well below the 0.5 pathogenic threshold, consistent with tolerated prediction). BayesDel score -0.327 (negative, predicting benign effect). SpliceAI max delta 0.00 (no predicted impact on splicing). Three orthogonal in silico approaches converge on a benign or neutral prediction.
REVEL: 0.131 (tolerated/benign).BayesDel: -0.326833 (benign prediction).SpliceAI: max delta 0.00 (no splice impact).
Assessed · not applied
Pathogenic
PS1
No pathogenic variant causing the same amino acid change (p.Leu277Val) via a different nucleotide change has been identified in ClinVar or the literature.
PS2
No de novo occurrence data are available for this variant.
PS3
No variant-specific functional studies have been reported for NM_002878.4:c.829C>G (p.Leu277Val).
PS4
No case-control or cohort data demonstrating enrichment of this variant in affected individuals versus controls are available.
PM1
Position 277 in RAD51D does not lie within a statistically significant mutational hotspot (cancerhotspots.org negative).
PM5
PM5 candidate harvesting did not identify any same-residue pathogenic comparator variants at position 277 in RAD51D.
PM6
No de novo occurrence of this variant has been reported.
PP1
No cosegregation data are available for this variant.
PP2
PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease.
PP3
Multiple lines of computational evidence suggest this variant is tolerated, not deleterious.
PP4
No patient phenotype or family history data are provided in the case materials.
PP5
ClinVar classification for this variant is Uncertain significance (Variation ID 539856), with review status 'criteria provided, single submitter' (1-star).
Benign
BA1
The variant is extremely rare in population databases.
BS1
The variant allele frequency (gnomAD ~0.0004%) is far below the BS1 threshold of >0.3% for a dominant disorder.
BS2
No data are available demonstrating observation of this variant in healthy adults at an age when the disease would be expected to have manifested with full penetrance.
BS3
No well-established functional studies demonstrate that this variant has no damaging effect on protein function or splicing.
BS4
No family segregation data are available to demonstrate lack of cosegregation with disease.
BP1
BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease.
BP2
No observation of this variant in trans with a known pathogenic variant in RAD51D has been reported.
BP5
No data are available showing this variant in a case with an alternative molecular basis for disease.
BP6
ClinVar classification for this variant is Uncertain significance, not benign.
N/A · 2
PVS1 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.71732e-06; MAF= 0.00037%, 6/1614064 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08456e-06; MAF= 0.00051%, 6/1180042 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
v2.1
This variant is present in gnomAD v2.1 (AF= 3.977e-06; MAF= 0.00040%, 1/251446 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.7926e-06; MAF= 0.00088%, 1/113732 alleles, homozygotes = 0).
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.00037%
· 6 / 1,614,064
0 hom · FAF 0.00018%
0 hom · FAF 0.00018%
European (non-Finnish) 6 / 1,180,042 |
0.00051% |
+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.0004%
· 1 / 251,446
0 hom
0 hom
European (non-Finnish) 1 / 113,732 |
0.00088% |
+ 7 not observed (African/African American, Admixed 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 (3 clinical laboratories). (ClinVarID = 539856)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.131. BayesDel score = -0.326833.
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. RAD51D, a DNA repair protein, is infrequently altered in cancer.
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 · 2 PMIDs not cited in assessment
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
25394175 ↗
A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.
CLINVAR