RAD51B c.428C>T (p.Thr143Ile) is observed at very low frequency in population databases (gnomAD v2.1: AF=0.0091%, 25/274,618 alleles; v4.1: AF=0.0039%, 63/1,602,290 alleles; no homozygotes), meeting PM2 at moderate strength.1 This is a missense variant and does not qualify for PVS1 under the ClinGen SVI framework (PMC6185798), as it is not a nonsense, frameshift, or canonical splice site variant.2 No variant-specific functional data, case-control studies, de novo observations, co-segregation data, or same-residue comparator variants were identified. In silico predictions are conflicting (REVEL 0.603, BayesDel 0.189, SpliceAI 0.01) and do not meet PP3 or BP4 thresholds.3 ClinVar reports this variant as Uncertain significance (1★, single submitter: Ambry Genetics). No 3★ expert panel classification exists to support PP5 or BP6.4 With only PM2 (moderate) met and all other criteria not met or not applicable, there is insufficient evidence to classify this variant beyond Uncertain Significance under ACMG/AMP 2015 rules (PMID:25741868). This is consistent with the ClinVar classification.5
RAD51B
Final classification
VUS
RAD51B c.428C>T · p.Thr143Ile
RAD51B
RAD51B c.428C>T (p.Thr143Ile) is observed at very low frequency in population databases (gnomAD v2.1: AF=0.0091%, 25/274,618 alleles; v4.1: AF=0.0039%, 63/1,602,290 alleles; no homozygotes), meeting PM2 at moderate strength.
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 moderate; combination = 1 moderate, which maps to VUS.
Classification rationale
PM2
VUS
RAD51B c.428C>T
PM2
→
VUS
2
pvs1_generic_framework ↗pvs1_variant_assessment
3
revelbayesdelspliceai ↗oncokb ↗
5
generic_acmg_combination_rules
Gene diagram
· NM_133509.4 · variants mapped to exon structure
RAD51B
NM_133509.4
Fetching transcript structure from UCSC…
Applied criteria · 1 applied · 23 assessed
Applied · 1
Strength
Supporting
Moderate
Strong
Very strong
✓
PM2
moderate
Pathogenic
This variant is present in gnomAD at very low frequency (v2.1: AF=0.0091%, 25/274,618 alleles; v4.1: AF=0.0039%, 63/1,602,290 alleles; highest subpopulation AF=0.062% in South Asian, v2.1), well below the 0.1% threshold for PM2 in non-VCEP context. No homozygotes observed.
gnomAD v2.1 total AF = 0.0091% (< 0.1% threshold)gnomAD v4.1 total AF = 0.0039% (< 0.1% threshold)Highest subpopulation AF = 0.062% (South Asian
Assessed · not applied
Pathogenic
PVS1
This missense variant (p.Thr143Ile) does not fall into the ClinGen SVI PVS1 null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus).
PS1
No alternative nucleotide change at codon 143 producing the same amino acid substitution (Thr143Ile) was identified as pathogenic in ClinVar or the literature.
PS2
No de novo observation with confirmed parentage reported for this variant.
PS3
No variant-specific functional data identified.
PS4
The variant has been observed in general population databases (gnomAD, 25–63 alleles) without case-control comparison showing enrichment in affected individuals.
PM1
Residue 143 does not fall within a statistically significant cancer hotspot (cancerhotspots.org) and no gene-specific literature establishes this position as a critical functional domain enriched for pathogenic missense variants.
PM5
No pathogenic missense comparator variant at the same codon (position 143) was identified in ClinVar.
PM6
No de novo observation reported for this variant (with or without confirmed parentage).
PP1
No co-segregation data available for this variant in affected families.
PP2
Insufficient evidence that RAD51B has a low rate of benign missense variation and that missense is a common mechanism of disease.
PP3
In silico predictions show conflicting results: REVEL score of 0.603 is moderately above the damaging threshold (0.5), but BayesDel score of 0.189 falls in the benign range (<0.27), and SpliceAI predicts no splicing impact (max delta=0.01).
PP4
No proband phenotype or family history data are available to assess specificity for a RAD51B-associated disorder.
PP5
ClinVar classification for this variant is Uncertain significance (1★, criteria provided, single submitter).
Benign
BA1
Maximum population allele frequency (0.062% South Asian, gnomAD v2.1) is well below the 1% BA1 threshold.
BS1
Maximum population allele frequency (0.062% South Asian, gnomAD v2.1) is below the 0.3% BS1 threshold.
BS2
No evidence that this variant has been observed in healthy adult individuals in a context permitting BS2 application (e.g., homozygous state or comprehensive healthy cohort data).
BS3
No well-established functional studies demonstrating no damaging effect of this variant on protein function or splicing.
BS4
No family segregation data available to demonstrate lack of co-segregation with disease.
BP1
RAD51B is a homologous recombination repair gene where both truncating and missense variants are reported in the literature.
BP2
No evidence that this variant has been observed in trans with a known pathogenic variant in RAD51B or another gene for a fully penetrant dominant disorder.
BP4
Multiple lines of computational evidence do not consistently support a benign effect.
BP5
No alternate molecular basis for disease has been identified in an individual carrying this variant.
BP6
ClinVar classification for this variant is Uncertain significance (1★), not benign or likely benign.
N/A · 2
BP3 · BP7
Research & evidence
Population frequency
gnomAD v4.1
gnomAD v2.1
v4.1
This variant is present in gnomAD v4.1 (AF= 3.93187e-05; MAF= 0.00393%, 63/1602290 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.00055164; MAF= 0.05516%, 49/88826 alleles, homozygotes = 0); grpmax FAF= 0.00042809.
v2.1
This variant is present in gnomAD v2.1 (AF= 9.10355e-05; MAF= 0.00910%, 25/274618 alleles, homozygotes = 0) and has highest observed frequency in the South Asian population (AF= 0.000621547; MAF= 0.06215%, 18/28960 alleles, homozygotes = 0); grpmax FAF= 0.00040121.
🇨🇦 CA
Absent from gnomAD-Canada v1.0.
Allele frequency by ancestry
three datasets · side by side
gnomAD v4.1
0.0039%
· 63 / 1,602,290
0 hom · FAF 0.043%
0 hom · FAF 0.043%
South Asian 49 / 88,826 |
0.055% |
Remaining individuals 3 / 61,940 |
0.0048% |
African/African American 2 / 74,286 |
0.0027% |
European (non-Finnish) 9 / 1,174,820 |
0.00077% |
+ 6 not observed (Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish)
gnomAD v2.1
0.0091%
· 25 / 274,618
0 hom · FAF 0.04%
0 hom · FAF 0.04%
South Asian 18 / 28,960 |
0.062% |
European (non-Finnish) 6 / 126,106 |
0.0048% |
African/African American 1 / 24,678 |
0.0041% |
+ 5 not observed (Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals)
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 (1 clinical laboratory). (ClinVarID = 3786390)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.603. BayesDel score = 0.189466.
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; COSV108918756, n = 1 times).
Hotspots
This variant does not lie in a statistically significant hotspot.
Sources & reference links