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 applied · 18 assessed
Applied · 3
Strength
Supporting
Moderate
Strong
Very strong
✓
BS1
strong
Benign
The gnomAD v4.1 grpmax filtering allele frequency is 0.89%, exceeding the 0.3% BS1 threshold for generic non-VCEP ACMG adjudication. The Middle Eastern subpopulation allele frequency is 1.11% with 1 homozygote. In aggregate across v4.1, 2 homozygotes are observed in 1,613,538 alleles (621 total alleles). For a cancer predisposition gene where pathogenic variants are expected to be rare, this population frequency and the presence of homozygotes in ostensibly healthy population controls strongly supports a benign interpretation.
gnomAD v4.1 grpmax FAF 0.89% (>0.3% BS1 threshold)Middle Eastern subpopulation AF 1.11% with 1 homozygoteSouth Asian subpopulation AF 0.107% with 1 homozygote
✓
BP4
supporting
Benign
Multiple lines of computational evidence consistently predict no impact on gene product: REVEL score 0.017 (well below 0.5 deleterious threshold), BayesDel score -0.558 (negative = benign), and SpliceAI max delta score 0.03 (no predicted splicing alteration). All available in silico tools concur in a benign assessment.
REVEL 0.017 (benign)BayesDel -0.558 (benign)SpliceAI max delta 0.03 (no splice impact).
✓
BP6
supporting
Benign
Ambry Genetics, a reputable clinical diagnostic laboratory, has classified this variant as Likely benign with criteria provided (ClinVar accession SCV005488250). While the review status is 'criteria provided, single submitter' and not an expert panel consensus, the classification from a clinical testing laboratory with established variant interpretation practices supports a benign interpretation.
ClinVar SCV005488250: Ambry Genetics classifies as Likely benign (criteria providedclinical testing).
Assessed · not applied
Pathogenic
PS1
No previously established pathogenic variant resulting in the same amino acid change (p.Ala76Thr) has been identified in ClinVar or the literature.
PS2
No de novo occurrence with confirmed paternity and maternity has been reported for this variant in the available literature or ClinVar submissions.
PS3
No well-established functional studies demonstrating a damaging effect have been identified for this variant.
PS4
No case-control or cohort data demonstrating statistically significant enrichment of this variant in affected individuals versus controls has been identified.
PM1
Residue Ala76 does not lie within a statistically significant mutational hotspot in RAD51B, nor within a well-established critical functional domain defined by a RAD51B-specific VCEP framework.
PM2
Although the overall allele frequency in gnomAD v2.1 (0.042%) and v4.1 (0.038%) is below the 0.1% PM2 threshold, gnomAD v4.1 reports 2 homozygotes and a grpmax filtering allele frequency of 0.89% (>0.3% BS1 threshold).
PM6
No de novo occurrence (without confirmed paternity and maternity) has been reported for this variant in ClinVar submissions or the available literature.
PP1
No co-segregation data with disease in multiple affected family members is available for this variant.
PP2
PP2 assessment requires gene-level constraint metrics (e.g., missense Z-score from gnomAD) to determine whether RAD51B has a low rate of benign missense variation and whether missense variants are a common mechanism of disease.
PP3
Multiple in silico predictors consistently indicate a benign effect: REVEL score 0.017 (well below the 0.5 threshold for deleterious prediction), BayesDel score -0.558 (negative = benign), and SpliceAI max delta 0.03 (no predicted splicing impact).
PP4
No patient phenotype or clinical history data are available for this variant.
PP5
No reputable source has classified this variant as pathogenic.
Benign
BA1
The overall allele frequency in gnomAD v4.1 is 0.038%, and the highest subpopulation frequency (Middle Eastern) is 1.11%.
BS3
No well-established functional studies demonstrating no damaging effect have been identified for this variant.
BS4
No family segregation data demonstrating lack of co-segregation with disease is available for this variant.
BP1
BP1 applies to missense variants in genes where only truncating variants are known to cause disease.
BP2
No observation of this variant in trans with a pathogenic variant for a fully penetrant dominant disorder, or in cis with a pathogenic variant for a recessive disorder, has been reported.
BP5
No observation of this variant in a case where an alternate molecular basis for disease has been identified.
N/A · 4
PVS1 · PM5 · BS2 · BP7
Research & evidence
Population frequency · supports benign
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 0.000384869; 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