NM_133509.4:c.226G>A (p.Ala76Thr) is a missense variant in exon 4 of RAD51B that is present in gnomAD v4.1 at a grpmax filtering allele frequency of 0.89%, exceeding the BS1 threshold of 0.3%, with 2 homozygotes observed in the general population.1 Multiple in silico predictors consistently indicate a benign effect for this amino acid substitution: REVEL score 0.017, BayesDel score -0.558, and SpliceAI max delta 0.03, meeting BP4 at supporting benign strength.2 Ambry Genetics, a clinical diagnostic laboratory, has classified this variant as Likely benign (ClinVar SCV005488250, criteria provided), meeting BP6 at supporting benign strength.3 No pathogenic criteria are met. PVS1 is not applicable as the variant is missense. PS1-PS4, PM1-PM2, PM6, PP1-PP5, BS3-BS4, and BP1-BP2 are either not met or not applicable.4
RAD51B
Final classification
Likely Benign
RAD51B c.226G>A · p.Ala76Thr
RAD51B
NM_133509.4:c.226G>A (p.Ala76Thr) is a missense variant in exon 4 of RAD51B that is present in gnomAD v4.1 at a grpmax filtering allele frequency of 0.89%, exceeding the BS1 threshold of 0.3%, with 2 homozygotes observed in the general population.
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 strong benign, BP4 supporting benign, BP6 supporting benign; combination = 1 strong benign + 2 supporting benign, which maps to Likely Benign.
Classification rationale
BS1BP4BP6
Likely Benign
RAD51B c.226G>A
BS1 + BP4 + BP6
→
Likely Benign
2
revelbayesdelspliceai ↗
4
clinvar ↗pm5_candidatespvs1_variant_assessment
Gene diagram
· NM_133509.4 · variants mapped to exon structure
RAD51B
NM_133509.4
Fetching transcript structure from UCSC…
Applied criteria · 3 met · select any tile
Met
Not met
Not assessed
N/A
Strength
very strong
supporting
Pathogenic evidence
PVS
PS
PM
PP
Benign evidence
BA
BS
BP
—
—
—
Rationale
Select a criterion.
Sources
Evidence used
Gaps remaining
Rule
—
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000384869; MAF= 0.03849%, 621/1613538 alleles, homozygotes = 2) and has highest observed frequency in the Middle Eastern population (AF= 0.0110598; MAF= 1.10598%, 67/6058 alleles, homozygotes = 1); grpmax FAF= 0.00893491.
v2.1
This variant is present in gnomAD v2.1 (AF= 0.000424385; MAF= 0.04244%, 120/282762 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.00110834; MAF= 0.11083%, 8/7218 alleles, homozygotes = 0); grpmax FAF= 0.00070522.
🇨🇦 CA
This variant is present in gnomAD-Canada v1.0 (AF= 0.0011943539630836048, 22/18420 alleles, homozygotes = 0).
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.038%
· 621 / 1,613,538
2 hom · FAF 0.89%
2 hom · FAF 0.89%
Middle Eastern 67 / 6,058 |
1.1% 1 hom |
Admixed American 80 / 59,992 |
0.13% |
South Asian 97 / 91,058 |
0.11% 1 hom |
Remaining individuals 34 / 62,494 |
0.054% |
European (non-Finnish) 326 / 1,179,564 |
0.028% |
African/African American 15 / 74,990 |
0.02% |
Ashkenazi Jewish 2 / 29,600 |
0.0068% |
+ 3 not observed (European (Finnish), Amish, East Asian)
gnomAD v2.1
0.042%
· 120 / 282,762
0 hom · FAF 0.071%
0 hom · FAF 0.071%
Remaining individuals 8 / 7,218 |
0.11% |
South Asian 30 / 30,614 |
0.098% |
Admixed American 27 / 35,404 |
0.076% |
European (non-Finnish) 52 / 129,126 |
0.04% |
Ashkenazi Jewish 3 / 10,368 |
0.029% |
+ 3 not observed (African/African American, East Asian, European (Finnish))
gnomAD Canada 🇨🇦
0.12%
· 22 / 18,420
0 hom · FAF 0.072%
0 hom · FAF 0.072%
Remaining individuals 7 / 1,138 |
0.62% |
European (non-Finnish) 14 / 11,740 |
0.12% |
South Asian 1 / 1,362 |
0.073% |
+ 6 not observed (African/African American, Latino/Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Middle Eastern)
ClinVar
This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory) and as Likely benign (1 clinical laboratory). (ClinVarID = 584552)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.03). REVEL score = 0.017. BayesDel score = -0.557559.
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; COSV66842132, n = 1 times).
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