About RAD51
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAD51 c.235C>T, p.(Arg79Cys)
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
PM2Supporting
PM2 · supporting
NM_133487.3:c.235C>T is present at very low frequency in gnomAD population databases: v2.1 AF = 0.01847% (9/48,718 alleles) and v4.1 AF = 0.01668% (37/221,888 alleles), both well below the 0.1% PM2 threshold. Absent from gnomAD-Canada in the adjusted call set. No homozygotes observed.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple in silico prediction tools suggest NM_133487.3:c.235C>T (p.Arg79Cys) has no deleterious effect. REVEL score is 0.025 (strongly benign-leaning), BayesDel score is -0.556 (negative; consistent with benign), and SpliceAI predicts no splicing impact (max delta 0.07).
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 supporting, BP4 supporting; combination = 1 supporting + 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
37 / 221,888 alleles
gnomAD v4.1: 37 / 221,888 alleles. Recorded AF 0.000166751. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000184737; MAF= 0.01847%, 9/48718 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000938673; MAF= 0.09387%, 3/3196 alleles, homozygotes = 0); grpmax FAF= 0.00032823.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00013335111348179759, 2/14998 alleles, homozygotes = 0).
SpliceAI score
0.070 maximum delta
Recorded SpliceAI maximum delta score: 0.070. 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. RAD51, a DNA repair protein, is recurrently altered by mutation or amplification in pancreatic and breast cancers.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV104569496, 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.
29 criteria with recorded statuses: 2 met · 5 not met · 14 not assessed · 8 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
Met
Not met
Not assessed
Not applicable
NM_133487.3:c.235C>T (p.Arg79Cys) is a rare missense variant in RAD51, present at very low frequency in gnomAD (v2.1: 0.018%; v4.1: 0.017%) with no homozygotes observed, meeting PM2 at supporting level.
Multiple in silico prediction tools (REVEL 0.025, BayesDel -0.556, SpliceAI max delta 0.07) do not support a deleterious effect, meeting BP4 at supporting level.
The variant is absent from ClinVar and has not been reported in the germline literature. No functional studies, segregation data, case-control comparisons, or de novo observations are available.
Residue Arg79 is located in the N-terminal domain, outside the functionally critical RecA-like ATPase core (Walker A/B motifs), and is not in a statistically significant mutational hotspot.
Applying the generic ACMG/AMP 2015 final combination rules (PMID:25741868), the evidence comprises one supporting pathogenic criterion (PM2) and one supporting benign criterion (BP4). These are insufficient to reach a classification of Likely Pathogenic, Likely Benign, Pathogenic, or Benign. The variant is classified as a Variant of Uncertain Significance (VUS).
No criteria match.
Met · 2
PM2 SupportingNM_133487.3:c.235C>T is present at very low frequency in gnomAD population databases: v2.1 AF = 0.01847% (9/48,718 alleles) and v4.1 AF = 0.01668% (37/221,888 alleles), both well below the 0.1% PM2 threshold. Absent from gnomAD-Canada in the adjusted call set. No homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF 0.01847% (9/48
- 718
- 0 hom)
- grpmax FAF 0.0328%
- gnomAD v4.1: AF 0.01668% (37/221
- 888
- grpmax FAF 0.0163%
- gnomAD-Canada: absent from adjusted call set.
Sources
BP4 SupportingMultiple in silico prediction tools suggest NM_133487.3:c.235C>T (p.Arg79Cys) has no deleterious effect. REVEL score is 0.025 (strongly benign-leaning), BayesDel score is -0.556 (negative; consistent with benign), and SpliceAI predicts no splicing impact (max delta 0.07). Details ▾Hide ▴
Evidence considered
- REVEL: 0.025 (non-deleterious)
- BayesDel: -0.5557 (benign-leaning)
- SpliceAI max delta: 0.07 (no splice impact).
Sources
Not met · 5 · evaluated, threshold not reached
PM1 Codon 79 (p.Arg79) is located in the N-terminal region of RAD51, outside the RecA-like ATPase domain that contains the functionally critical Walker A and Walker B motifs. Cancer Hotspots analysis confirmed that this residue is not in a statistically significant mutational hotspot. Details ▾Hide ▴
Evidence considered
- Cancer Hotspots: residue R79 not significant
- exact variant not listed. Position lies within the N-terminal domain (residues ~1-95)
- not the ATPase core domain containing known critical functional motifs.
Sources
PP3 Multiple in silico prediction tools do not support a deleterious effect for NM_133487.3:c.235C>T (p.Arg79Cys). REVEL score is 0.025 (well below the typical supporting threshold of 0.5), BayesDel score is -0.556 (negative; benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.07). Details ▾Hide ▴
Evidence considered
- REVEL: 0.025 (non-deleterious)
- BayesDel: -0.5557 (benign-leaning)
- SpliceAI max delta: 0.07 (no splice impact).
Sources
BA1 The highest population allele frequency for NM_133487.3:c.235C>T is 0.0939% in the Admixed American population (gnomAD v2.1), which does not exceed the 1% BA1 threshold. Details ▾Hide ▴
Evidence considered
- Max population AF: 0.0939% in AMR (gnomAD v2.1)
- 0.0231% in NFE (gnomAD v4.1). Both far below 1% BA1 threshold.
Sources
BS1 The highest population allele frequency for NM_133487.3:c.235C>T is 0.0939% in the Admixed American population (gnomAD v2.1), which does not exceed the 0.3% BS1 threshold for non-VCEP adjudication. Details ▾Hide ▴
Evidence considered
- Max population AF: 0.0939% in AMR (gnomAD v2.1)
- 0.0231% in NFE (gnomAD v4.1). Both below the 0.3% BS1 threshold.
Sources
BP1 While loss-of-function is an established disease mechanism for RAD51, missense variants are also reported in RAD51-associated disease. The gene does not have a predominantly truncating disease mechanism; both missense and truncating variants are implicated in RAD51-related phenotypes. Details ▾Hide ▴
Evidence considered
- RAD51 LOF mechanism supported (PMID:42232598
- PMID:20400963)
- but missense variants are also a recognized disease mechanism (PMID:20400963 reports homozygous missense in RAD51C paralog causing FA-like disorder)
- both variant types contribute to RAD51-related phenotypes.
Sources
pvs1_gene_context
Not assessed · 14 · no assessment recorded
PS1 No known pathogenic variant at the same nucleotide position (c.235) was identified for comparison. ClinVar is absent for this variant and no alternative nucleotide change at this position was found in the evidence sources. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no alternative nucleotide substitutions at c.235 identified.
Still missing
- No comparator variant at c.235 available for PS1 evaluation.
Sources
PS2 No de novo evidence is available for NM_133487.3:c.235C>T. Neither ClinVar nor the literature search identified any report of this variant occurring de novo with confirmed maternity and paternity. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar or literature.
Still missing
- No family studies or de novo data available for this variant.
Sources
PS3 No variant-specific functional studies were identified for NM_133487.3:c.235C>T (p.Arg79Cys). OncoKB reports Unknown Oncogenic Effect with no variant-level reviewed functional evidence. No literature publications with functional characterization of this variant were found. Details ▾Hide ▴
PS4 No case-control studies or disease-specific cohort data are available for NM_133487.3:c.235C>T. The variant is absent from ClinVar and no publications reporting case-control comparisons were identified. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no case-control or cohort enrichment data in the literature.
Still missing
- No case-control data or disease prevalence comparisons available.
Sources
PM5 No known pathogenic missense variant at the same residue (Arg79) was identified. PM5 candidate harvesting was unable to establish classic same-residue pathogenicity semantics for this variant. Details ▾Hide ▴
Evidence considered
- PM5 candidate harvesting found no same-residue pathogenic comparators at Arg79 in ClinVar.
Still missing
- No pathogenic variant at codon 79 available for PM5 comparison.
Sources
pm5_candidatesclinvar ↗
PM6 No de novo evidence is available for NM_133487.3:c.235C>T. Neither ClinVar nor the literature search identified any report of this variant as a de novo occurrence. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar or literature.
Still missing
- No de novo observations reported for this variant.
Sources
PP1 No co-segregation data are available for NM_133487.3:c.235C>T. No family studies reporting segregation of this variant with disease were identified in the literature or ClinVar. Details ▾Hide ▴
Evidence considered
- No segregation or family study data identified.
Still missing
- No segregation analysis available.
Sources
PP2 Insufficient gene-level constraint data are available to evaluate whether RAD51 has a low rate of benign missense variation. No Z-score, Missense Constraint (Mis-Z), or other constraint metrics were retrieved for this gene in the evidence pipeline. Details ▾Hide ▴
Evidence considered
- No constraint metrics (Z-score
- gnomAD missense constraint) available for RAD51.
Still missing
- Gene-level missense constraint data not available.
PP4 No patient phenotype or family history information is available for NM_133487.3:c.235C>T. The variant has not been reported in a clinical context in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No clinical phenotype or family history data available.
Still missing
- Patient phenotype data not provided for evaluation.
Sources
BS2 No clinical data on healthy adult carriers of NM_133487.3:c.235C>T are available. No homozygous or hemizygous observations have been reported in population databases or clinical sources. Details ▾Hide ▴
Evidence considered
- No homozygotes observed in gnomAD
- no clinical data on healthy adult carriers.
Still missing
- No clinical phenotype data on carriers to assess for unaffected status.
Sources
BS3 No variant-specific functional studies were identified for NM_133487.3:c.235C>T (p.Arg79Cys). No in vitro or in vivo assays demonstrating a neutral functional effect are available. Details ▾Hide ▴
Evidence considered
- OncoKB reports Unknown Oncogenic Effect
- no functional studies demonstrating neutral effect identified.
Still missing
- No functional studies showing no damaging effect on protein function.
Sources
BS4 No segregation data are available for NM_133487.3:c.235C>T. No family studies demonstrating lack of co-segregation with disease were identified. Details ▾Hide ▴
Evidence considered
- No family segregation data available.
Still missing
- No co-segregation analysis available to assess for non-segregation.
Sources
BP2 No phase information is available for NM_133487.3:c.235C>T. No observations in trans or cis with known pathogenic variants have been reported in ClinVar or the literature. Details ▾Hide ▴
Evidence considered
- No phase data (in trans or in cis) available.
Still missing
- No observations in trans with pathogenic variants to support BP2.
Sources
BP5 No clinical data on alternative molecular diagnoses are available for carriers of NM_133487.3:c.235C>T. The variant has not been reported in cases with an alternate molecular basis for disease. Details ▾Hide ▴
Evidence considered
- No data on alternative molecular diagnoses in variant carriers.
Still missing
- No clinical data on alternative molecular basis for disease.
Sources
Not applicable · 8· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_133487.3:c.235C>T is a missense variant (p.Arg79Cys) and does not fall into the null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants required for PVS1 under the ClinGen SVI PVS1 framework (PMC6185798). Details ▾Hide ▴
Evidence considered
- Missense variant classified in the 'other' variant bucket by the PVS1 decision tree
- apply_generic_pvs1_framework is false.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
PM3 N/ANo phase information or observations in trans with pathogenic variants are available for NM_133487.3:c.235C>T. PM3 assessment requires phase-resolved data not present in this case. Details ▾Hide ▴
PM4 N/ANM_133487.3:c.235C>T is a missense substitution, not a non-frame-shifting insertion/deletion or stop-loss variant. PM4 applies to protein-length-altering changes outside of stop-loss. Details ▾Hide ▴
Evidence considered
- Missense variant
- not a non-frame-shifting indel or stop-loss.
PP5 N/ANo reputable source has classified NM_133487.3:c.235C>T as pathogenic. The variant is absent from ClinVar. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no external pathogenic classification exists.
Sources
BP3 N/ANM_133487.3:c.235C>T is a missense substitution, not an in-frame indel. BP3 applies to in-frame deletions/insertions in non-repeat regions. Details ▾Hide ▴
Evidence considered
- Missense variant
- not an in-frame indel.
BP6 N/ANo reputable source has classified NM_133487.3:c.235C>T as benign. The variant is absent from ClinVar. Details ▾Hide ▴
BP7 N/ANM_133487.3:c.235C>T is a missense variant (p.Arg79Cys), not a synonymous/intronic variant. BP7 applies exclusively to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous.
PS5 N/ANo reputable source has classified NM_133487.3:c.235C>T as pathogenic. The variant is absent from ClinVar entirely. Details ▾Hide ▴
Evidence considered
- Absent from ClinVar
- no external pathogenic classification exists.
Sources
Identifiers
- Gene
- RAD51
- Transcript
- NM_133487.3
- Coding (HGVS c.)
- NM_133487.3:c.235C>T
- Protein (HGVS p.)
- NP_597994.3:p.(Arg79Cys)
- GRCh38
- chr15:40701815 C>T
- GRCh37
- chr15:40994013 C>T
- COSMIC
- COSV104569496
Gene diagram
Every interpreted variant in RAD51, mapped onto the exon structure of NM_133487.3. Select a row to find it on the plot.
RAD51NM_133487.3
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 RAD51
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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
37 / 221,888 alleles
AF 0.000167 · 0 homozygotes · FAF 0.000163
gnomAD v2.1
9 / 48,718 alleles
AF 0.000185 · 0 homozygotes · FAF 0.000328
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 0.00017 · 37 / 221,888 alleles · 0 hom · FAF 0.00016
| European (non-Finnish)27 / 116,728 | 0.00023 |
| Admixed American3 / 15,106 | 0.0002 |
| African/African American5 / 34,426 | 0.00015 |
| European (Finnish)1 / 11,274 | 8.9e-05 |
| South Asian1 / 24,716 | 4e-05 |
0 alternate alleles recorded in 5 other groups: Remaining individuals, Amish, East Asian, Middle Eastern, Ashkenazi Jewish.
gnomAD v2.1
AF 0.00018 · 9 / 48,718 alleles · 0 hom · FAF 0.00033
| Admixed American3 / 3,196 | 0.00094 |
| European (non-Finnish)6 / 23,094 | 0.00026 |
0 alternate alleles recorded in 6 other groups: African/African American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
gnomAD-Canada
AF not recorded · ? / ? alleles
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 0.000166751; MAF= 0.01668%, 37/221888 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000231307; MAF= 0.02313%, 27/116728 alleles, homozygotes = 0); grpmax FAF= 0.00016303.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000184737; MAF= 0.01847%, 9/48718 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000938673; MAF= 0.09387%, 3/3196 alleles, homozygotes = 0); grpmax FAF= 0.00032823.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00013335111348179759, 2/14998 alleles, homozygotes = 0).
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.025
- BayesDel
- -0.556
How the predictions were used
BP4 SupportingMultiple in silico prediction tools suggest NM_133487.3:c.235C>T (p.Arg79Cys) has no deleterious effect. REVEL score is 0.025 (strongly benign-leaning), BayesDel score is -0.556 (negative; consistent with benign), and SpliceAI predicts no splicing impact (max delta 0.07). Details ▾Hide ▴
Evidence considered
- REVEL: 0.025 (non-deleterious)
- BayesDel: -0.5557 (benign-leaning)
- SpliceAI max delta: 0.07 (no splice impact).
Sources
PP3 Multiple in silico prediction tools do not support a deleterious effect for NM_133487.3:c.235C>T (p.Arg79Cys). REVEL score is 0.025 (well below the typical supporting threshold of 0.5), BayesDel score is -0.556 (negative; benign-leaning), and SpliceAI predicts no splicing impact (max delta 0.07). Details ▾Hide ▴
Evidence considered
- REVEL: 0.025 (non-deleterious)
- BayesDel: -0.5557 (benign-leaning)
- SpliceAI max delta: 0.07 (no splice impact).
Sources
BP7 N/ANM_133487.3:c.235C>T is a missense variant (p.Arg79Cys), not a synonymous/intronic variant. BP7 applies exclusively to synonymous variants without predicted splice impact. Details ▾Hide ▴
Evidence considered
- Missense substitution
- not synonymous.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.025. BayesDel score = -0.555735.
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
37 / 221,888 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.070
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_133487.3%3Ac.235C%3ET
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/15-40994013-C-T?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr15-40701815-C-T?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/15-40701815-C-T
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_133487.3%3Ac.235C…
- OncoKB ↗www.oncokb.org/gene/RAD51/R79C
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=142613741
- 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= 0.000166751; MAF= 0.01668%, 37/221888 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000231307; MAF= 0.02313%, 27/116728 alleles, homozygotes = 0); grpmax FAF= 0.00016303.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 0.000184737; MAF= 0.01847%, 9/48718 alleles, homozygotes = 0) and has highest observed frequency in the Admixed American population (AF= 0.000938673; MAF= 0.09387%, 3/3196 alleles, homozygotes = 0); grpmax FAF= 0.00032823.
gnomAD-Canada
This variant is present in gnomAD-Canada v1.0 (AF= 0.00013335111348179759, 2/14998 alleles, homozygotes = 0).
ClinVar
This variant is absent from ClinVar.
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.07). REVEL score = 0.025. BayesDel score = -0.555735.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RAD51, a DNA repair protein, is recurrently altered by mutation or amplification in pancreatic and breast cancers.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV104569496, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.