About RAD51B
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAD51B c.428C>T, p.(Thr143Ile)
Classification
Uncertain significance
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is uncertain. Select a step to read what it means.
Uncertain.The recorded classification is uncertain significance.
In plain language
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.
LYFE Sciences is an AI system, and it can make mistakes.
Criteria may be applied incorrectly, sources may be misread, and a
confident-looking classification can still be wrong.
Double-check every criterion and its underlying evidence
before relying on any call.
01The reasoning
How it was classified
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
Recorded applied criteria
The applied criteria and their strengths are shown as assessed under the stated framework.
Pathogenic evidence criteria: 1
Benign evidence criteria: 0
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
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.
Benign criteria applied · 0
No benign criterion marked as applied in the recorded assessment.
Recorded classification: Uncertain significance
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.
02The sources
Evidence at a glance
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1
gnomAD v2.1
Population frequency
63 / 1,602,290 alleles
gnomAD v4.1: 63 / 1,602,290 alleles. Recorded AF 3.93187e-05. Recorded homozygote count 0.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.010 maximum delta
Recorded SpliceAI maximum delta score: 0.010. Refer to the recorded PP3/BP4 rationale for interpretation.
No listed criterion applied
SpliceAI ↗
ClinVar submissions
1 reported laboratory submissions
1 Uncertain significance. ClinVar API review status: criteria provided, single submitter.
Context only
ClinVar ↗
Functional evidence
Statement recorded
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.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV108918756, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.
Context only
For specialists
Technical detail
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
27 criteria with recorded statuses: 1 met · 24 not met · 0 not assessed · 2 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
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.
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.
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.
ClinVar reports this variant as Uncertain significance (1★, single submitter: Ambry Genetics). No 3★ expert panel classification exists to support PP5 or BP6.
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.
No criteria match.
Met · 1
PM2 ModerateThis 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. Details ▾Hide ▴
Evidence considered
- 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
- v2.1)
- grpmax FAF = 0.04% (v2.1)
- 0.043% (v4.1)
- 0 homozygotes in both datasets
Sources
Not met · 24 · evaluated, threshold not reached
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). The generic PVS1 framework (PMC6185798) does not apply to missense substitutions. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution (c.428C>T
- p.Thr143Ile) in exon 5/11
- Not a nonsense
- frameshift
- or canonical splice site variant
- ClinGen SVI PVS1 decision tree (PMC6185798) does not assign PVS1 to missense variants
Sources
PS1 No alternative nucleotide change at codon 143 producing the same amino acid substitution (Thr143Ile) was identified as pathogenic in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found no same-residue comparator variants for position 143
Sources
pm5_candidates
PS2 No de novo observation with confirmed parentage reported for this variant. Details ▾Hide ▴
Still missing
- No de novo studies available
PS3 No variant-specific functional data identified. OncoKB reports unknown oncogenic effect with no cited PMIDs, COSMIC records one somatic occurrence (COSV108918756) but somatic presence alone does not constitute functional evidence for germline PS3. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence
- COSMIC: 1 somatic observation (COSV108918756) — not functional data
Still missing
- No functional studies identified for p.Thr143Ile
- No systematic range characterization of RAD51B residue 143
Sources
PS4 The variant has been observed in general population databases (gnomAD, 25–63 alleles) without case-control comparison showing enrichment in affected individuals. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 25/274
- 618 alleles (AF=0.0091%)
- gnomAD v4.1: 63/1
- 602
- 290 alleles (AF=0.0039%)
- No case-control or odds-ratio data available
Still missing
- No affected vs. control comparison data
Sources
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. The nearby Walker A motif (residues ~128–135) is upstream; position 143 is outside the characterized ATP-binding domain. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: residue not statistically significant
- Position 143 is 8 residues downstream of the Walker A ATP-binding motif (residues ~128–135)
- No domain-specific functional characterization of residues near position 143 identified
Still missing
- No RAD51B domain-specific functional data for residues surrounding position 143
PM5 No pathogenic missense comparator variant at the same codon (position 143) was identified in ClinVar. Automated PM5 candidate search returned no candidates. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvest returned 0 same-residue candidates
- Unable to confirm classic same-residue PM5 semantics
Still missing
- No comparator missense variant at p.143 identified
Sources
pm5_candidates
PM6 No de novo observation reported for this variant (with or without confirmed parentage). Details ▾Hide ▴
Still missing
- No de novo reports available
PP1 No co-segregation data available for this variant in affected families. Details ▾Hide ▴
Still missing
- No family segregation data
PP2 Insufficient evidence that RAD51B has a low rate of benign missense variation and that missense is a common mechanism of disease. RAD51B is a large gene where both truncating and missense variants occur; gene-level constraint data were not assessed in this evaluation. Details ▾Hide ▴
Evidence considered
- RAD51B missense constraint metrics not evaluated
Still missing
- No gene-level missense constraint data (e.g.
- Z-score
- o/e)
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). Multiple lines of computational evidence do not consistently support a deleterious effect, and therefore PP3 is not met. Details ▾Hide ▴
Evidence considered
- REVEL = 0.603 (above damaging threshold of 0.5)
- BayesDel = 0.189 (below damaging threshold of 0.27
- benign range)
- SpliceAI max delta = 0.01 (no predicted splicing impact)
Still missing
- Conflicting in silico predictions prevent meeting PP3
Sources
PP4 No proband phenotype or family history data are available to assess specificity for a RAD51B-associated disorder. Details ▾Hide ▴
Still missing
- No proband phenotype or clinical history provided
PP5 ClinVar classification for this variant is Uncertain significance (1★, criteria provided, single submitter). PP5 requires a reputable source reporting the variant as pathogenic, and per global rule the ClinVar expert panel must be 3★ to qualify at supporting strength. Neither condition is met. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- 1★ (criteria provided
- single submitter — Ambry Genetics)
- No expert panel or 3★ review-level pathogenic classification
Sources
BA1 Maximum population allele frequency (0.062% South Asian, gnomAD v2.1) is well below the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- Max subpopulation AF = 0.062% (South Asian
- v2.1)
- < 1% BA1 threshold
Sources
BS1 Maximum population allele frequency (0.062% South Asian, gnomAD v2.1) is below the 0.3% BS1 threshold. Details ▾Hide ▴
Evidence considered
- Max subpopulation AF = 0.062% (South Asian
- v2.1)
- < 0.3% BS1 threshold
Sources
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). Details ▾Hide ▴
Still missing
- No healthy adult cohort observation data
BS3 No well-established functional studies demonstrating no damaging effect of this variant on protein function or splicing. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta = 0.01 (no predicted splice impact
- but insufficient as stand-alone BS3 evidence)
- No protein-level functional studies (e.g.
- HR repair assay
- protein interaction)
Still missing
- No functional assays performed on p.Thr143Ile
Sources
BS4 No family segregation data available to demonstrate lack of co-segregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data
BP1 RAD51B is a homologous recombination repair gene where both truncating and missense variants are reported in the literature. While germline truncating variants have been described (PMID:25600502), there is insufficient evidence that RAD51B disease is primarily mediated by truncating variants to apply BP1 to this missense change. Details ▾Hide ▴
Evidence considered
- RAD51B is a DNA repair gene
- both truncating and missense variants have been implicated
- BP1 requires a gene where primarily truncating variants cause disease — not established for RAD51B
Sources
pvs1_gene_context
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. Details ▾Hide ▴
No further detail was recorded.
BP4 Multiple lines of computational evidence do not consistently support a benign effect. While BayesDel (0.189) falls in the benign range and SpliceAI (0.01) predicts no splicing impact, REVEL (0.603) predicts a damaging effect. Conflicting in silico predictions preclude application of BP4. Details ▾Hide ▴
Evidence considered
- REVEL = 0.603 (damaging prediction
- contradicts BP4)
- BayesDel = 0.189 (benign range)
- SpliceAI max delta = 0.01 (no splicing impact)
Still missing
- Conflicting in silico predictions prevent meeting BP4
Sources
BP5 No alternate molecular basis for disease has been identified in an individual carrying this variant. Details ▾Hide ▴
Still missing
- No clinical case data with alternate molecular diagnosis
BP6 ClinVar classification for this variant is Uncertain significance (1★), not benign or likely benign. BP6 requires a reputable source reporting the variant as benign, and per global rule the ClinVar submission must be 3★ expert panel to qualify. Neither condition is met. Details ▾Hide ▴
Evidence considered
- ClinVar: Uncertain significance
- 1★ (criteria provided
- single submitter)
- No benign/likely benign classification from an expert panel
Sources
PS5 No reputable source has recently reported this variant as pathogenic with inaccessible evidence. Details ▾Hide ▴
Evidence considered
- ClinVar classification: Uncertain significance
- single submitter (Ambry Genetics)
- No expert panel or multi-submitter pathogenic call
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
BP3 N/AIn-frame indels only; this is a substitution variant. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ASynonymous variants only; this is a missense substitution (c.428C>T, p.Thr143Ile). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- RAD51B
- Transcript
- NM_133509.4
- Coding (HGVS c.)
- NM_133509.4:c.428C>T
- Protein (HGVS p.)
- NP_598193.2:p.(Thr143Ile)
- GRCh38
- chr14:67865115 C>T
- GRCh37
- chr14:68331832 C>T
- ClinVar
- 3786390
- COSMIC
- COSV108918756
Gene diagram
Every interpreted variant in RAD51B, mapped onto the exon structure of NM_133509.4. Select a row to find it on the plot.
RAD51BNM_133509.4
Fetching transcript structure from UCSC…
Exons
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Transcript span
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Strand
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Variants mapped
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Source
UCSC ncbiRefSeqCurated
All variants in RAD51B
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Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
63 / 1,602,290 alleles
AF 3.93e-05 · 0 homozygotes · FAF 0.000428
gnomAD v2.1
25 / 274,618 alleles
AF 9.1e-05 · 0 homozygotes · FAF 0.000401
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.9e-05 · 63 / 1,602,290 alleles · 0 hom · FAF 0.00043
| South Asian49 / 88,826 | 0.00055 |
| Remaining individuals3 / 61,940 | 4.8e-05 |
| African/African American2 / 74,286 | 2.7e-05 |
| European (non-Finnish)9 / 1,174,820 | 7.7e-06 |
0 alternate alleles recorded in 6 other groups: Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 9.1e-05 · 25 / 274,618 alleles · 0 hom · FAF 0.0004
| South Asian18 / 28,960 | 0.00062 |
| European (non-Finnish)6 / 126,106 | 4.8e-05 |
| African/African American1 / 24,678 | 4.1e-05 |
0 alternate alleles recorded in 5 other groups: Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals.
Statements
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.603
- BayesDel
- 0.189
How the predictions were used
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). Multiple lines of computational evidence do not consistently support a deleterious effect, and therefore PP3 is not met. Details ▾Hide ▴
Evidence considered
- REVEL = 0.603 (above damaging threshold of 0.5)
- BayesDel = 0.189 (below damaging threshold of 0.27
- benign range)
- SpliceAI max delta = 0.01 (no predicted splicing impact)
Still missing
- Conflicting in silico predictions prevent meeting PP3
Sources
BP4 Multiple lines of computational evidence do not consistently support a benign effect. While BayesDel (0.189) falls in the benign range and SpliceAI (0.01) predicts no splicing impact, REVEL (0.603) predicts a damaging effect. Conflicting in silico predictions preclude application of BP4. Details ▾Hide ▴
Evidence considered
- REVEL = 0.603 (damaging prediction
- contradicts BP4)
- BayesDel = 0.189 (benign range)
- SpliceAI max delta = 0.01 (no splicing impact)
Still missing
- Conflicting in silico predictions prevent meeting BP4
Sources
BP7 N/ASynonymous variants only; this is a missense substitution (c.428C>T, p.Thr143Ile). Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.01). REVEL score = 0.603. BayesDel score = 0.189466.
0 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
63 / 1,602,290 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.010
Open source ↗
ClinVar
1 Uncertain significance
Open source ↗
COSMIC
Captured COSMIC source record
Open source ↗
Cancer hotspots
Captured Cancer Hotspots source record
Open source ↗
OncoKB
Captured OncoKB source record
Open source ↗
All source links
- ClinVar ↗www.ncbi.nlm.nih.gov/clinvar/variation/3786390/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/14-68331832-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr14-67865115-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/14-67865115-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_133509.4%3Ac.428C…
- OncoKB ↗www.oncokb.org/gene/RAD51B/T143I
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=172508456
- Cancer hotspots ↗www.cancerhotspots.org/
Statements for reports
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
gnomAD 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.
gnomAD 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.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
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
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.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV108918756, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.