NM_133509.4:c.476G>A (p.Arg159His) in RAD51B is classified as Likely benign based on three supporting benign criteria per the generic ACMG/AMP 2015 framework (PMID:25741868). The generic ACMG combination rules require ≥2 supporting benign criteria for Likely benign classification.1 The variant exceeds the 0.3% BS1 allele frequency threshold in the South Asian subpopulation (gnomAD v2.1 SAS AF = 0.358%, 109/30,430 alleles, 1 homozygote; gnomAD v4.1 SAS AF = 0.337%, 305/90,530 alleles, 3 homozygotes; grpmax FAF = 0.303%), indicating it is too common to be a highly penetrant pathogenic variant (BS1_supporting).2 Multiple in silico tools predict a benign impact: REVEL score 0.385 (below 0.5 threshold), BayesDel score 0.129 (near-zero), and SpliceAI max delta 0.00 (no splice impact), meeting BP4_supporting.3 ClinVar reports this variant as Likely benign from three clinical testing laboratories (Ambry Genetics, PreventionGenetics, NHLS; Variation ID 1678949), meeting BP6_supporting.4 No pathogenic or likely pathogenic criteria were met. PVS1 does not apply to this missense variant. PS3/PS4 are not met due to absence of variant-specific functional or case-control data. PM2 is not met as the variant frequency exceeds 0.1% in the South Asian population. PP3 is not met because all in silico tools predict a benign effect. PP5 is not met as ClinVar reports Likely benign, not pathogenic.
RAD51B
Final classification
Likely Benign
RAD51B c.476G>A · p.Arg159His
RAD51B
NM_133509.4:c.476G>A (p.Arg159His) in RAD51B is classified as Likely benign based on three supporting benign criteria per the generic ACMG/AMP 2015 framework (PMID:25741868). The generic ACMG combination rules require ≥2 supporting benign criteria for Likely benign classification.
gene-specific framework lacked a usable explicit final combination framework, so generic ACMG/AMP 2015 final-combination rules were applied as fallback; applied criteria: BS1 supporting, BP4 supporting, BP6 supporting; combination = 3 supporting benign, which maps to Likely Benign.
Classification rationale
BS1BP4BP6
Likely Benign
RAD51B c.476G>A
BS1 + BP4 + BP6
→
Likely Benign
Gene diagram
· NM_133509.4 · variants mapped to exon structure
RAD51B
NM_133509.4
Fetching transcript structure from UCSC…
Applied criteria · 3 applied · 20 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
supporting
Benign
This variant exceeds the 0.3% allele frequency threshold for a presumed dominant disorder in the South Asian subpopulation. In gnomAD v2.1, the SAS AF is 0.358% (109/30,430 alleles) with 1 homozygote, and in gnomAD v4.1, the SAS AF is 0.337% (305/90,530 alleles) with 3 homozygotes. The grpmax filtering allele frequency is 0.303% (v2.1). The presence of homozygous individuals in a population database further supports that this variant is too common to be a highly penetrant pathogenic variant. Assessed at supporting strength rather than strong benign due to the population-specific nature of the elevated frequency.
gnomAD v2.1 SAS: AF=0.358% (>0.3%)109/30430
✓
BP4
supporting
Benign
Multiple lines of computational evidence consistently predict no damaging effect: REVEL score 0.385 (below the published 0.5 threshold for pathogenicity), BayesDel score 0.129 (near-zero, consistent with benign impact), and SpliceAI max delta score 0.00 (no predicted splice alteration). All available in silico tools agree on a benign prediction.
REVEL: 0.385 (below 0.5 damaging thresholdbenign-leaning)BayesDel: 0.129 (near-zero
✓
BP6
supporting
Benign
This variant is classified as Likely benign in ClinVar (Variation ID 1678949) by three clinical laboratories: Ambry Genetics, PreventionGenetics (part of Exact Sciences), and the National Health Laboratory Service. While the review status is 'criteria provided, single submitter' and no expert panel review has been performed, the consensus from multiple clinical testing laboratories supports a benign interpretation.
ClinVar Variation ID 1678949: Likely benign from 3 clinical laboratoriesSubmitters: Ambry GeneticsPreventionGenetics/Exact Sciences
Assessed · not applied
Pathogenic
PVS1
NM_133509.4:c.476G>A is a missense variant (p.Arg159His), not a null variant (nonsense, frameshift, or canonical ±1,2 splice site).
PS1
No evidence that the same amino acid change (p.Arg159His) has been previously established as pathogenic via a different nucleotide change.
PS2
No de novo reports for NM_133509.4:c.476G>A were identified in ClinVar submissions, literature, or public databases.
PS3
No variant-specific functional evidence was identified.
PS4
No case-control or cohort studies reporting enrichment of NM_133509.4:c.476G>A in affected versus unaffected individuals were identified.
PM1
This variant (p.Arg159His) is not located in a statistically significant mutational hotspot and does not lie within a well-established critical functional domain with supporting literature evidence for missense constraint.
PM2
This variant is present in gnomAD v2.1 at an overall allele frequency of 0.042% (118/281,876 alleles) and in the South Asian subpopulation at 0.358% (109/30,430 alleles), exceeding the PM2 threshold of <0.1%.
PM6
No de novo evidence for NM_133509.4:c.476G>A was identified.
PP1
No segregation data for NM_133509.4:c.476G>A were identified in any reviewed publication or database.
PP2
PP2 requires a low rate of benign missense variation in the gene and missense variants as a common disease mechanism.
PP3
Multiple in silico tools predict a benign impact for this variant.
PP4
Patient-specific phenotype and family history data were not provided for this assessment.
PP5
ClinVar reports this variant as Likely benign (3 clinical laboratories; ClinVar Variation ID 1678949), not pathogenic.
Benign
BA1
The overall allele frequency in gnomAD v2.1 is 0.042% and in gnomAD v4.1 is 0.024%, both well below the BA1 threshold of >1%.
BS2
While this variant is observed in population databases (gnomAD), BS2 requires observation in a healthy adult individual for a disorder expected to be fully penetrant at an early age.
BS3
No functional studies specifically assessing the impact of NM_133509.4:c.476G>A (p.Arg159His) on RAD51B protein function were identified.
BS4
No segregation data for NM_133509.4:c.476G>A were identified in any reviewed publication.
BP1
BP1 requires that the gene has a disease mechanism primarily through truncating variants and that the specific missense variant is in a gene where missense changes are not a known cause of disease.
BP2
No data on observation of NM_133509.4:c.476G>A in trans with a known pathogenic RAD51B variant.
BP5
No data identifying an alternate molecular basis for disease in a case harboring NM_133509.4:c.476G>A was identified.
N/A · 2
PM5 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000238735; MAF= 0.02387%, 384/1608480 alleles, homozygotes = 3) and has highest observed frequency in the South Asian population (AF= 0.00336905; MAF= 0.33690%, 305/90530 alleles, homozygotes = 3); grpmax FAF= 0.00305752.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000418624; MAF= 0.04186%, 118/281876 alleles, homozygotes = 1) and has highest observed frequency in the South Asian population (AF= 0.00358199; MAF= 0.35820%, 109/30430 alleles, homozygotes = 1); grpmax FAF= 0.00303643.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0006515365403409708, 12/18418 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.024%
· 384 / 1,608,480
3 hom · FAF 0.31%
3 hom · FAF 0.31%
South Asian 305 / 90,530 |
0.34% 3 hom |
Remaining individuals 18 / 62,184 |
0.029% |
Admixed American 14 / 59,870 |
0.023% |
Middle Eastern 1 / 6,028 |
0.017% |
European (non-Finnish) 43 / 1,176,150 |
0.0037% |
European (Finnish) 2 / 63,862 |
0.0031% |
East Asian 1 / 44,766 |
0.0022% |
+ 3 not observed (Amish, Ashkenazi Jewish, African/African American)
gnomAD v2.1
0.042%
· 118 / 281,876
1 hom · FAF 0.3%
1 hom · FAF 0.3%
South Asian 109 / 30,430 |
0.36% 1 hom |
Remaining individuals 2 / 7,188 |
0.028% |
Admixed American 4 / 35,218 |
0.011% |
European (Finnish) 2 / 25,080 |
0.008% |
European (non-Finnish) 1 / 128,786 |
0.00078% |
+ 3 not observed (African/African American, Ashkenazi Jewish, East Asian)
gnomAD Canada 🇨🇦
0.065%
· 12 / 18,418
0 hom · FAF 0.51%
0 hom · FAF 0.51%
South Asian 12 / 1,362 |
0.88% |
+ 8 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern, European (non-Finnish), Remaining individuals)
ClinVar
This variant has been reported in ClinVar as Likely benign (3 clinical laboratories). (ClinVarID = 1678949)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.385. BayesDel score = 0.129411.
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. RAD51B, a DNA repair protein involved in homologous recombination, is altered by mutation in various cancer types.
COSMIC
Cancer hotspots
Somatic evidence
Not in COSMIC / hotspots
COSMIC
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV66846898, n = 2 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links
Triaged references · 6 PMIDs not cited in assessment
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
17392385 ↗
American Cancer Society guidelines for breast screening with MRI as an adjunct to mammography.
CLINVAR
23788249 ↗
ACMG recommendations for reporting of incidental findings in clinical exome and genome sequencing.
CLINVAR
26324357 ↗
American Society of Clinical Oncology Policy Statement Update: Genetic and Genomic Testing for Cancer Susceptibility.
CLINVAR