Classification rationale

PM2 BP3BP4 Likely Benign

RAD51B c.171_173dup in_frame_indel_unknown · exon 3

PM2 (Supporting): present once in 1,612,890 gnomAD v4.1 alleles, indicating extreme rarity. BP3 (Supporting): in-frame duplication of one CAG repeat unit in a tandem repeat region with no known function. BP4 (Supporting): SpliceAI max delta 0.09, below the ~0.2 high-precision cutoff. Likely Benign: under generic ACMG/AMP 2015 rules, the two supporting benign criteria outweigh the single supporting pathogenic criterion (PM2).

PM2 + BP3 + BP4 → 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 · 18 assessed

MetEvidence satisfies this criterion.

Not metEvaluated against available evidence; threshold not reached.

Not assessedApplies in principle, but no evidence was found to evaluate it.

N/ADoesn't apply to this variant type.

Applied · 3

Strength Supporting Moderate Strong Very strong

✓

PM2 supporting review Pathogenic

Met (supporting): seen once in gnomAD v4.1 (1 in 1,612,890 alleles), indicating extreme rarity.

gnomAD v4.1 reports 1 alternate allele among 1,612,890 total alleles (AF 6.20005e-07), with 0 homozygotes; the highest displayed subpopulation AF is 1.09963e-05 in South Asians and 4.31704e-05 in South Asian females.gnomAD v2.1 reports 1 alternate allele among 250,880 total alleles (AF 3.98597e-06), with 0 homozygotes; the highest displayed subpopulation AF is 3.28386e-05 in South Asians and 1.33333e-04 in South Asian females.gnomAD-Canada v1.0 reports the variant as absent.

gnomad_v2 ↗gnomad_v4 ↗gnomad_canada ↗

✓

BP3 supporting Benign

Met (supporting): in-frame duplication of one CAG repeat unit in a tandem repeat region with no known function.

ClinVar variation 3942256 variant title 'NM_133510.4(RAD51B):c.168CAG[3] (p.Ser57_Arg58insSer)' confirms the variant is an expansion of a tandem CAG repeat from 2 to 3 copies, i.e., an in-frame insertion in a repeat region.Transcript-level verification against the NM_133509.4 reference sequence (NCBI): c.168-173 = CAGCAG (tandem CAG repeat); c.171_173dupCAG yields CAGCAGCAG and an in-frame single Ser insertion (p.Ser57dup). The affected residue (Ser57) is in exon 3, N-terminal region, upstream of the Walker A ATPase motif (GPPGCGKT) which begins at residue ~108.pvs1_variant_assessment.json: consequence_class=in_frame_indel_unknown, canonical_splice_consensus=false — the change is an in-frame insertion with no NMD or splice-consensus involvement.

clinvar ↗

✓

BP4 supporting Benign

Met (supporting): SpliceAI max delta 0.09, below the ~0.2 high-precision cutoff.

SpliceAI scores for NM_133509.4:c.171_173dup: DS_AG=0.09, DS_AL=0.001, DS_DG=0.001, DS_DL=0.003, max_delta_score=0.09; Pangolin SG=0.032, SL=-0.005 (source: spliceai, evidence.json splicing block).The SpliceAI developers (Jaganathan KK et al., Cell 2019, PMID 30661751) reported that delta scores below ~0.2 correspond to predicted absence of splice-altering effect at high precision; a max delta of 0.09 is well within this benign-predicted range.REVEL and BayesDel are not applicable to this in-frame duplication variant class and are recorded as not found/null in the case evidence, so they contribute no additional BP4 signal here.

spliceai ↗

Assessed · not applied · 7 not met · 11 not assessed

Pathogenic

PS2 Not assessed: no de novo observation or parental testing was available.

PS3 Not assessed: no functional assay data on this variant were available.

PS4 Not assessed: no case-control or prevalence data for this variant were available.

PM3 Not assessed: no biallelic or phase evidence was available.

PM4 Not met: the in-frame insertion lies within a tandem CAG repeat region, where BP3 applies instead.

PM6 Not assessed: no documented de novo occurrence.

PP1 Not assessed: no familial segregation data were available.

PP3 Not met: SpliceAI max delta 0.09, below the ~0.2 high-precision threshold.

PP4 Not assessed: no patient phenotype data were provided.

PP5 Not met: ClinVar reports only a single-submitter uncertain-significance record, not an expert-panel pathogenic classification.

Benign

BA1 Not met: gnomAD v4.1 total frequency 6.2e-07, far below the 1% stand-alone benign threshold.

BS1 Not met: highest population frequency 0.013%, below the 0.3% BS1 threshold.

BS2 Not met: no homozygous carriers were observed.

BS3 Not assessed: no functional assay data on this variant were available.

BS4 Not assessed: no non-segregation evidence was available.

BP2 Not assessed: no trans/cis phase information was available.

BP5 Not assessed: no alternative molecular diagnosis was documented.

BP6 Not met: ClinVar reports only a single-submitter uncertain-significance record, not an expert-panel benign classification.

N/A · 7 PVS1 · PS1 · PM1 · PM5 · PP2 · BP1 · BP7

Research & evidence

Population frequency · supports benign

gnomAD v4.1

gnomAD v2.1

v4.1

This variant is present in gnomAD v4.1 (AF= 6.20005e-07; MAF= 0.00006%, 1/1612890 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 1.09963e-05; MAF= 0.00110%, 1/90940 alleles, homozygotes = 0).

v2.1

This variant is present in gnomAD v2.1 (AF= 3.98597e-06; MAF= 0.00040%, 1/250880 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 3.28386e-05; MAF= 0.00328%, 1/30452 alleles, homozygotes = 0).

🇨🇦 CA

Absent from gnomAD-Canada v1.0.

Allele frequency by ancestry

three datasets · side by side

gnomAD v4.1

6.2e-05% · 1 / 1,612,890
0 hom

South Asian

1 / 90,940

0.0011%

+ 9 not observed (Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish, African/African American, European (non-Finnish))

gnomAD v2.1

0.0004% · 1 / 250,880
0 hom

South Asian

1 / 30,452

0.0033%

+ 7 not observed (African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), European (non-Finnish), Remaining individuals)

gnomAD Canada 🇨🇦

Absent · 0 / ?
0 hom

Not observed in any ancestry group.

gnomAD v4 ↗ gnomAD v2 ↗ gnomAD 🇨🇦 ↗

ClinVar

This variant has been reported in ClinVar as Uncertain significance (1 clinical laboratory). (ClinVarID = 3942256)

ClinVar ↗

In silico

SpliceAI predicts no significant splice impact for this variant (max delta score = 0.09).

SpliceAI ↗

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.

OncoKB ↗

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.

COSMIC ↗ Hotspots ↗

Sources & reference links

8Sources

ClinVar

gnomAD v2.1

gnomAD v4.1

gnomAD-Canada

SpliceAI

OncoKB

COSMIC

Cancer hotspots