About RAD51B
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAD51B c.121G>A, p.(Val41Met)
Classification
Likely benign
Variant description:
No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely benign. Select a step to read what it means.
Likely benign.A likely benign classification under the recorded framework.
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: 2
Pathogenic criteria applied · 1
PM2Supporting
PM2 · supporting
Extremely low population frequency: gnomAD v4.1 AF = 6.20e-07 (1/1,613,612 alleles, no homozygotes). Absent from gnomAD v2.1 and gnomAD-Canada. Well below the 0.1% PM2 threshold for rare diseases.
Benign criteria applied · 2
BP1Supporting
BP1 · supporting
Missense variant (p.Val41Met) in RAD51B, a gene in which loss-of-function truncating variants are the established germline disease mechanism. Published germline RAD51B mutations associated with melanoma and breast/ovarian cancer predisposition are predominantly truncating or splice-disrupting.
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest no impact on gene product: REVEL score 0.039 (benign), BayesDel score -0.491 (benign), and SpliceAI max delta 0.13 (no significant splice impact). All in silico predictors are concordant for a benign effect.
Recorded classification: Likely benign
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 supporting, BP1 supporting, BP4 supporting; combination = 1 supporting + 2 supporting benign, which maps to Likely Benign.
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
1 / 1,613,612 alleles
gnomAD v4.1: 1 / 1,613,612 alleles. Recorded AF 6.19728e-07. Recorded homozygote count 0.
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.130 maximum delta
Recorded SpliceAI maximum delta score: 0.130. 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.
26 criteria with recorded statuses: 3 met · 9 not met · 11 not assessed · 3 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.121G>A (p.Val41Met) is a missense variant in RAD51B, a gene in which loss-of-function truncating variants are the established germline disease mechanism for melanoma and breast/ovarian cancer predisposition.
This variant is extremely rare in population databases: present at an allele frequency of 6.20e-07 in gnomAD v4.1 (1/1,613,612 alleles) and absent from gnomAD v2.1 and gnomAD-Canada, meeting PM2 at supporting strength.
Multiple in silico predictors are concordant for a benign effect: REVEL score 0.039 (benign), BayesDel score -0.491 (benign), and SpliceAI max delta 0.13 (no splice impact), meeting BP4 at supporting strength.
As a missense variant in a gene where truncating variants are the primary pathogenic mechanism, BP1 applies at supporting strength.
The variant is absent from ClinVar; no functional studies, segregation data, case-control data, or de novo observations are available. No publications specifically mention NM_133509.4:c.121G>A.
With one supporting pathogenic criterion (PM2) and two supporting benign criteria (BP1, BP4), the net evidence is insufficient to classify this variant as either pathogenic or benign. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 3
PM2 SupportingExtremely low population frequency: gnomAD v4.1 AF = 6.20e-07 (1/1,613,612 alleles, no homozygotes). Absent from gnomAD v2.1 and gnomAD-Canada. Well below the 0.1% PM2 threshold for rare diseases. Details ▾Hide ▴
Evidence considered
- gnomAD v4.1: 1 allele out of 1
- 613
- 612 (AF = 6.20e-07)
- highest in NFE at 8.48e-07
- gnomAD v2.1: absent
- gnomAD-Canada v1.0: absent
Sources
BP1 SupportingMissense variant (p.Val41Met) in RAD51B, a gene in which loss-of-function truncating variants are the established germline disease mechanism. Published germline RAD51B mutations associated with melanoma and breast/ovarian cancer predisposition are predominantly truncating or splice-disrupting. Details ▾Hide ▴
Evidence considered
- RAD51B germline disease mechanism: loss-of-function via truncating variants (PMID:25600502)
- Published germline RAD51B mutations are predominantly nonsense and splicing variants
Sources
pvs1_gene_context
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product: REVEL score 0.039 (benign), BayesDel score -0.491 (benign), and SpliceAI max delta 0.13 (no significant splice impact). All in silico predictors are concordant for a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.039 (benign
- well below ~0.5 threshold)
- BayesDel: -0.491 (negative score
- predicting benign)
- SpliceAI max delta: 0.13 (below 0.2 threshold
- no splice impact)
Sources
Not met · 9 · evaluated, threshold not reached
PS1 No pathogenic missense variant at the same amino acid position has been established in ClinVar or the literature to support PS1. Details ▾Hide ▴
Evidence considered
- Variant is absent from ClinVar
- no same-residue pathogenic comparators identified.
Still missing
- No established pathogenic variant at residue 41 of RAD51B.
Sources
PS3 No functional studies have been reported for NM_133509.4:c.121G>A (p.Val41Met). OncoKB reports Unknown Oncogenic Effect with no variant-specific curated functional evidence. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence identified.
Still missing
- No experimental functional data for this variant or a systematically characterized range that includes residue 41.
Sources
PM1 Residue 41 does not lie within a statistically significant mutational hotspot (cancerhotspots.org). No variant-specific domain-level functional characterization has been identified for this position. Details ▾Hide ▴
Evidence considered
- cancerhotspots.org: not a significant residue hotspot.
Still missing
- No evidence that residue 41 is located in a critical functional domain characterized at variant-level resolution.
PP3 Multiple in silico predictors support a benign impact: REVEL score 0.039 (well below pathogenic threshold of ~0.5), BayesDel score -0.491 (negative, predicting benign), SpliceAI max delta 0.13 (no significant splice impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.039 (benign)
- BayesDel: -0.491 (benign)
- SpliceAI max delta: 0.13 (no splice impact)
Sources
PP5 Absent from ClinVar; no reputable source has reported NM_133509.4:c.121G>A as pathogenic. Details ▾Hide ▴
Evidence considered
- ClinVar: no entry for this variant.
Still missing
- No ClinVar or expert panel classification.
Sources
BA1 gnomAD v4.1 allele frequency is 6.20e-07, far below the 1% BA1 threshold for standing benign variation. Details ▾Hide ▴
BS1 gnomAD v4.1 allele frequency is 6.20e-07, far below the 0.3% BS1 threshold for benign standing variation in rare disease genes. Details ▾Hide ▴
BS3 No experimental functional studies demonstrating a neutral effect have been reported for this variant. In silico predictions alone do not satisfy BS3, which requires direct functional evidence. Details ▾Hide ▴
Evidence considered
- No functional studies identified for this variant.
Still missing
- No experimental functional data demonstrating no damaging effect.
BP6 Absent from ClinVar; no reputable source has reported NM_133509.4:c.121G>A as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: no entry for this variant.
Still missing
- No ClinVar or expert panel classification.
Sources
Not assessed · 11 · no assessment recorded
PS2 No de novo data are available for this variant. Details ▾Hide ▴
Still missing
- No parental testing or de novo confirmation data.
PS4 No case-control or enrichment data are available for this variant. Details ▾Hide ▴
Still missing
- No case-control studies or statistical enrichment data.
PM6 No de novo data are available for this variant. Details ▾Hide ▴
Still missing
- No de novo confirmation data.
PP1 No co-segregation data are available for this variant. Details ▾Hide ▴
Still missing
- No family segregation data.
PP2 No gene-level constraint data (e.g., missense Z-score, o/e ratio) are available to assess whether RAD51B has a low rate of benign missense variation. Details ▾Hide ▴
Still missing
- Missense constraint metrics not available for RAD51B.
PP4 No patient phenotype or family history data are available to assess disease specificity. Details ▾Hide ▴
Still missing
- No clinical phenotype data for the proband.
BS2 No data are available regarding observation in healthy adults independent of disease status. Details ▾Hide ▴
Still missing
- No data on observation in healthy adult controls.
BS4 No segregation data are available to assess lack of segregation with disease. Details ▾Hide ▴
Still missing
- No family segregation data.
BP2 No data are available regarding observation in trans with a pathogenic dominant variant. Details ▾Hide ▴
Still missing
- No data on trans configuration.
BP5 No alternate molecular basis for disease has been identified in this case. Details ▾Hide ▴
Still missing
- No alternate molecular basis data.
PS5 No data are available regarding observation in trans with a pathogenic variant for a recessive disorder. Details ▾Hide ▴
Still missing
- No trans configuration data.
Not applicable · 3· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/AMissense variant (p.Val41Met); does not fall into null-variant buckets (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 generic framework not applicable. Details ▾Hide ▴
Evidence considered
- Variant is a missense substitution in exon 3
- not a predicted null variant.
Sources
pvs1_variant_assessment
PM5 N/ANo same-residue pathogenic comparator variants identified in ClinVar; automatic PM5 candidate harvesting was unsuccessful. Details ▾Hide ▴
Evidence considered
- No pathogenic ClinVar entries at residue 41
- PM5 semantics could not be confirmed.
Sources
pm5_candidates
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a missense variant (c.121G>A, p.Val41Met). Details ▾Hide ▴
No further detail was recorded.
Identifiers
- Gene
- RAD51B
- Transcript
- NM_133509.4
- Coding (HGVS c.)
- NM_133509.4:c.121G>A
- Protein (HGVS p.)
- NP_598193.2:p.(Val41Met)
- GRCh38
- chr14:67825500 G>A
- GRCh37
- chr14:68292217 G>A
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
1 / 1,613,612 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
Allele count data not recorded
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,613,612 alleles · 0 hom
| European (non-Finnish)1 / 1,179,774 | 8.5e-07 |
0 alternate alleles recorded in 9 other groups: Remaining individuals, Admixed American, European (Finnish), Amish, East Asian, Middle Eastern, South Asian, Ashkenazi Jewish, African/African American.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.19728e-07; MAF= 0.00006%, 1/1613612 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.4762e-07; MAF= 0.00008%, 1/1179774 alleles, homozygotes = 0).
gnomAD v2.1
Absent from gnomAD v2.1.
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.039
- BayesDel
- -0.491
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest no impact on gene product: REVEL score 0.039 (benign), BayesDel score -0.491 (benign), and SpliceAI max delta 0.13 (no significant splice impact). All in silico predictors are concordant for a benign effect. Details ▾Hide ▴
Evidence considered
- REVEL: 0.039 (benign
- well below ~0.5 threshold)
- BayesDel: -0.491 (negative score
- predicting benign)
- SpliceAI max delta: 0.13 (below 0.2 threshold
- no splice impact)
Sources
PP3 Multiple in silico predictors support a benign impact: REVEL score 0.039 (well below pathogenic threshold of ~0.5), BayesDel score -0.491 (negative, predicting benign), SpliceAI max delta 0.13 (no significant splice impact). Details ▾Hide ▴
Evidence considered
- REVEL: 0.039 (benign)
- BayesDel: -0.491 (benign)
- SpliceAI max delta: 0.13 (no splice impact)
Sources
BP7 N/ABP7 applies to synonymous variants with no predicted splice impact. This is a missense variant (c.121G>A, p.Val41Met). Details ▾Hide ▴
No further detail was recorded.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.13). REVEL score = 0.039. BayesDel score = -0.491014.
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
1 / 1,613,612 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.130
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.121G%3EA
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/14-68292217-G-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr14-67825500-G-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/14-67825500-G-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_133509.4%3Ac.121G…
- OncoKB ↗www.oncokb.org/gene/RAD51B/V41M
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RAD51B+c.121G%3EA
- 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= 6.19728e-07; MAF= 0.00006%, 1/1613612 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.4762e-07; MAF= 0.00008%, 1/1179774 alleles, homozygotes = 0).
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 = 0.13). REVEL score = 0.039. BayesDel score = -0.491014.
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.