About RAD51B
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAD51B c.263C>G, p.(Ser88Cys)
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: 1
Pathogenic criteria applied · 1
PM2Moderate
PM2 · moderate
NM_133509.4:c.263C>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with PM2 under generic ACMG/AMP rules for a variant with population allele frequency below 0.1%.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on the gene product: SpliceAI predicts no splicing effect (max delta score 0.02), REVEL score of 0.055 is strongly benign-predicting, and BayesDel score of -0.479 is in the benign range. The convergence of independent in silico tools supports a lack of functional consequence for this missense change.
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, BP4 supporting benign; combination = 1 moderate + 1 supporting benign, 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
Not recorded
gnomAD v4.1 allele counts were not recorded for this variant.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.020 maximum delta
Recorded SpliceAI maximum delta score: 0.020. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
Not recorded
A ClinVar laboratory submission summary was not recorded.
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
No matching record reported
This variant has not previously been reported in somatic cancers (COSMIC).
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.
29 criteria with recorded statuses: 2 met · 22 not met · 0 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_133509.4:c.263C>G (p.Ser88Cys) in RAD51B is a missense variant absent from gnomAD v2.1, v4.1, and gnomAD-Canada population databases (PM2).
Multiple lines of in silico evidence — including REVEL (0.055), BayesDel (-0.479), and SpliceAI (max delta 0.02) — unanimously predict no damaging effect on the gene product (BP4).
The variant is absent from ClinVar and has not been reported in the literature. No functional, segregation, case-control, de novo, or phenotypic data are available.
With one moderate pathogenic criterion (PM2) and one supporting benign criterion (BP4), the evidence is insufficient to classify this variant as pathogenic, likely pathogenic, benign, or likely benign. The variant is classified as a Variant of Uncertain Significance (VUS) under generic ACMG/AMP 2015 guidelines.
No criteria match.
Met · 2
PM2 ModerateNM_133509.4:c.263C>G is absent from gnomAD v2.1, v4.1, and gnomAD-Canada, consistent with PM2 under generic ACMG/AMP rules for a variant with population allele frequency below 0.1%. Details ▾Hide ▴
Evidence considered
- Absent from gnomAD v2.1 (exomes)
- gnomAD v4.1 (exomes)
- and gnomAD-Canada v1.0 (genomes)
- allele frequency 0.0% in all populations
Sources
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: SpliceAI predicts no splicing effect (max delta score 0.02), REVEL score of 0.055 is strongly benign-predicting, and BayesDel score of -0.479 is in the benign range. The convergence of independent in silico tools supports a lack of functional consequence for this missense change. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.02 (no splicing impact)
- REVEL: 0.055 (benign)
- BayesDel: -0.479 (benign)
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No previously established pathogenic variant has been reported at amino acid position Ser88 in RAD51B. PS1 requires a known pathogenic variant with the same amino acid change arising from a different nucleotide substitution. Details ▾Hide ▴
Evidence considered
- ClinVar contains no entries for this variant
- PM5 candidate search found 0 same-residue comparator variants
Still missing
- No ClinVar or literature reports of any pathogenic variant at codon 88
Sources
clinvar ↗pm5_candidates
PS2 No de novo observation has been reported for this variant in any available source. PS2 requires confirmation of a de novo occurrence with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo data in ClinVar
- literature
- or any evidence source
Still missing
- No parental or trio sequencing data available
PS3 No functional studies have been performed on NM_133509.4:c.263C>G (p.Ser88Cys) or on a systematically characterized range encompassing codon 88. OncoKB reports unknown oncogenic effect with no variant-specific functional evidence. In silico predictions indicate no damaging effect (REVEL 0.055, BayesDel -0.479). Details ▾Hide ▴
Evidence considered
- OncoKB: unknown oncogenic effect
- REVEL 0.055 (benign-leaning)
- BayesDel -0.479 (benign-leaning)
- no PMIDs with functional data for this variant
Still missing
- No experimental functional studies available for this variant or a systematically characterized range containing codon 88
Sources
PS4 No case-control or cohort enrichment data are available for this variant. The variant is absent from gnomAD, limiting statistical comparisons, and absent from ClinVar, precluding any prevalence assessment in affected individuals. Details ▾Hide ▴
Evidence considered
- Absent from all gnomAD populations and ClinVar
- no case-control data available
Still missing
- No affected cohort data available to assess enrichment
Sources
PM1 Residue Ser88 does not lie within a statistically significant mutational hotspot in RAD51B (cancerhotspots.org). No domain-level evidence in the reviewed materials characterizes this region as a critical functional domain where missense variation is established as pathogenic. The N-terminal region of RAD51B preceding the Walker A motif (which begins around residue 106) has not been identified as a well-characterized functional domain for PM1 application. Details ▾Hide ▴
Evidence considered
- Cancerhotspots.org: residue not significant
- no literature evidence of a critical functional domain encompassing S88
Still missing
- No domain-specific functional characterization of the S88 region in RAD51B
PM5 No different pathogenic missense variant has been established at codon 88 (Ser88) of RAD51B. The automated PM5 candidate search identified zero same-residue comparator variants with expert panel or majority pathogenic classifications in ClinVar. Details ▾Hide ▴
Evidence considered
- 0 same-residue candidates
- 0 expert panel P/LP candidates
- 0 non-expert majority P/LP candidates
- no ClinVar entries at codon 88
Still missing
- No pathogenic comparator variants at the same amino acid residue
Sources
pm5_candidatesclinvar ↗
PM6 No de novo observation of this variant has been reported in any available source. PM6 requires a de novo occurrence without confirmation of paternity and maternity. Details ▾Hide ▴
Evidence considered
- No de novo reports in ClinVar
- gnomAD
- or any literature source
Still missing
- No trio or de novo sequencing data
PP1 No segregation data are available for this variant. PP1 requires cosegregation of the variant with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family or segregation data in any evidence source
Still missing
- No pedigree or cosegregation data
PP2 RAD51B is not represented in the HCI prior set, and no gene-specific data are available to establish that missense variants are a common mechanism of disease with a low rate of benign missense variation in this gene. The available PVS1 gene context literature supports truncating mutations in RAD51B-associated disease, but does not establish the PP2 premise for missense variants. Details ▾Hide ▴
Evidence considered
- HCI prior: gene not supported
- PVS1 gene context: disease mechanism identified for truncating variants
- not specifically for missense
Still missing
- No gene-specific missense constraint metric (e.g.
- missense Z-score) available
Sources
pvs1_gene_context
PP3 Multiple in silico tools unanimously predict a benign or no impact: REVEL score 0.055 (well below pathogenic threshold of 0.5), BayesDel score -0.479 (negative, benign), and SpliceAI max delta score 0.02 (no predicted splicing effect). No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.055 (benign)
- BayesDel: -0.479 (benign)
- SpliceAI: max delta 0.02 (no splicing impact)
Sources
PP4 No patient phenotype or clinical history is available for this variant. PP4 requires that the variant was identified in a patient whose phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No clinical phenotype data provided
Still missing
- No proband phenotype or clinical information
PP5 NM_133509.4:c.263C>G is absent from ClinVar. There is no reputable source recently classifying this variant as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: 0 variation IDs
- no classification
- no submitters
Still missing
- No ClinVar entry for this variant
Sources
BA1 The variant is absent from gnomAD (allele frequency 0.0%), which does not meet the BA1 threshold of >1% population allele frequency. BA1 requires a high allele frequency incompatible with disease causation. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: absent
- gnomAD v4.1 AF: absent
- gnomAD-Canada AF: 0/0
Sources
BS1 The variant is absent from gnomAD (allele frequency 0.0%), which does not meet the BS1 threshold of >0.3% population allele frequency. BS1 requires an allele frequency greater than expected for the disorder. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 AF: absent
- gnomAD v4.1 AF: absent
- gnomAD-Canada AF: 0/0
Sources
BS2 No evidence of this variant observed in a homozygous state, in trans with a pathogenic variant, or in healthy adult individuals is available. BS2 requires observation in such contexts without disease manifestations. Details ▾Hide ▴
Evidence considered
- No homozygous or healthy adult observations in any evidence source
Still missing
- No observations in healthy controls or homozygous state
BS3 No well-established in vitro or in vivo functional studies have been performed on this variant demonstrating no damaging effect on protein function or splicing. While in silico predictions are benign-leaning (REVEL 0.055, BayesDel -0.479), in silico data alone do not satisfy BS3, which requires experimental functional evidence. Details ▾Hide ▴
Evidence considered
- REVEL 0.055 (benign)
- BayesDel -0.479 (benign)
- no experimental functional studies available
Still missing
- No experimental functional studies for this variant
Sources
revelbayesdel
BS4 No segregation data are available to demonstrate lack of cosegregation with disease. BS4 requires observation of non-segregation in affected family members. Details ▾Hide ▴
Evidence considered
- No family or segregation data available
Still missing
- No pedigree or cosegregation data
BP1 BP1 applies when a missense variant occurs in a gene where primarily truncating variants are known to cause disease. While the PVS1 gene context literature supports RAD51B truncating mutations in melanoma and breast cancer predisposition, genome-wide association studies have also identified RAD51B missense and intronic variants associated with cancer risk, and the gene is not established as exclusively truncating-mediated. The available evidence does not support that only truncating variants cause RAD51B-associated disease. Details ▾Hide ▴
Evidence considered
- PVS1 gene context: truncating mutations reported
- but GWAS and broader literature suggest non-truncating RAD51B variation also associated with cancer risk
Still missing
- No definitive evidence that RAD51B disease is exclusively truncating-mediated
Sources
pvs1_gene_context
BP2 No evidence of this variant observed in trans with a known pathogenic variant in RAD51B or in cis with a pathogenic variant is available. BP2 requires such observations in the context of appropriate inheritance patterns. Details ▾Hide ▴
Evidence considered
- No trans or cis phase data available
Still missing
- No phasing or allelic observation data
BP5 No evidence is available of this variant being identified in a case with an alternate molecular basis for disease. BP5 requires a documented alternative genetic cause explaining the phenotype in a case where this variant was also found. Details ▾Hide ▴
Evidence considered
- No data on alternate molecular diagnoses in carriers of this variant
Still missing
- No co-occurring variant data or alternate molecular diagnosis data
BP6 NM_133509.4:c.263C>G is absent from ClinVar. No reputable source classifies this variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: no entry
- no classification
- no submitters
Still missing
- No ClinVar or other source classification for this variant
Sources
PS5 No alternative nucleotide change at codon 88 yielding the same missense change (p.Ser88Cys or another pathogenic change at this codon) has been reported as pathogenic. The PM5 candidate search identified no comparator variants at this residue. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found 0 same-residue candidates
- no ClinVar entries for any variant at codon 88
Still missing
- No known pathogenic alternative nucleotide change at codon 88
Sources
pm5_candidatesclinvar ↗
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/APVS1 is not applicable to missense variants. This variant is a substitution producing NP_598193.2:p.(Ser88Cys) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants defined by the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant c.263C>G (p.Ser88Cys)
- variant_bucket='other'
- apply_generic_pvs1_framework=false
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/APM3 applies to recessive disorders where the variant is observed in trans with a pathogenic variant. RAD51B-associated cancer predisposition is not a recessive disorder. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to protein-length-changing variants from in-frame deletions/insertions in non-repeat regions or stop-loss variants. This variant is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
BP3 N/ABP3 applies to in-frame deletions and insertions in repetitive regions. This variant is a single-nucleotide substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact. This variant is a missense substitution, NM_133509.4:c.263C>G (p.Ser88Cys), and is not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 criterion is restricted to synonymous variants
Identifiers
- Gene
- RAD51B
- Transcript
- NM_133509.4
- Coding (HGVS c.)
- NM_133509.4:c.263C>G
- Protein (HGVS p.)
- NP_598193.2:p.(Ser88Cys)
- GRCh38
- chr14:67835144 C>G
- GRCh37
- chr14:68301861 C>G
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
Allele count data not recorded
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
Statements
gnomAD v4.1
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.055
- BayesDel
- -0.479
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on the gene product: SpliceAI predicts no splicing effect (max delta score 0.02), REVEL score of 0.055 is strongly benign-predicting, and BayesDel score of -0.479 is in the benign range. The convergence of independent in silico tools supports a lack of functional consequence for this missense change. Details ▾Hide ▴
Evidence considered
- SpliceAI max delta: 0.02 (no splicing impact)
- REVEL: 0.055 (benign)
- BayesDel: -0.479 (benign)
Sources
PP3 Multiple in silico tools unanimously predict a benign or no impact: REVEL score 0.055 (well below pathogenic threshold of 0.5), BayesDel score -0.479 (negative, benign), and SpliceAI max delta score 0.02 (no predicted splicing effect). No computational evidence supports a deleterious effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.055 (benign)
- BayesDel: -0.479 (benign)
- SpliceAI: max delta 0.02 (no splicing impact)
Sources
BP7 N/ABP7 applies to synonymous (silent) variants for which splicing prediction algorithms predict no impact. This variant is a missense substitution, NM_133509.4:c.263C>G (p.Ser88Cys), and is not eligible for BP7. Details ▾Hide ▴
Evidence considered
- Missense variant
- BP7 criterion is restricted to synonymous variants
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.055. BayesDel score = -0.479357.
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
Captured gnomAD v4.1 source record
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.020
Open source ↗
ClinVar
Captured ClinVar source record
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/?term=NM_133509.4%3Ac.263C%3EG
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/14-68301861-C-G?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr14-67835144-C-G?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/14-67835144-C-G
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_133509.4%3Ac.263C…
- OncoKB ↗www.oncokb.org/gene/RAD51B/S88C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RAD51B+c.263C%3EG
- 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
Absent from gnomAD v4.1.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.02). REVEL score = 0.055. BayesDel score = -0.479357.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.