About RAD51D
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAD51D c.26G>T, p.(Cys9Phe)
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
This variant is extremely rare in population databases. gnomAD v2.1 reports 1 allele in 31,360 (AF=0.00319%), and gnomAD v4.1 reports 1 allele in 1,612,322 (AF=0.00006%). Both frequencies are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple lines of computational evidence suggest this variant does not impact protein function or splicing. REVEL score of 0.278 is well below the pathogenic threshold of 0.5. BayesDel score of 0.260 is weakly positive. SpliceAI predicts no splicing impact (max delta = 0.00). The weight of in silico evidence supports a benign interpretation.
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
1 / 1,612,322 alleles
gnomAD v4.1: 1 / 1,612,322 alleles. Recorded AF 6.20224e-07. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18878e-05; MAF= 0.00319%, 1/31360 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.49182e-05; MAF= 0.00649%, 1/15404 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI score
0.000 maximum delta
Recorded SpliceAI maximum delta score: 0.000. Refer to the recorded PP3/BP4 rationale for interpretation.
ClinVar submissions
5 reported laboratory submissions
5 Uncertain significance. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
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. RAD51D, a DNA repair protein, is infrequently altered in cancer.
No listed criterion applied
OncoKB ↗
COSMIC
Cancer Hotspots
Somatic evidence
1 recorded samples
This variant has previously been reported in somatic cancers (COSMIC; COSV50100981, 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 · 21 not met · 1 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_002878.3:c.26G>T (p.Cys9Phe) is a missense variant in exon 1 of RAD51D, a gene associated with autosomal dominant hereditary breast and ovarian cancer predisposition.
This variant is extremely rare in population databases: gnomAD v2.1 reports 1 allele in 31,360 (AF=0.00319%) and gnomAD v4.1 reports 1 allele in 1,612,322 (AF=0.00006%), meeting PM2 at supporting level.
Multiple lines of computational evidence (REVEL 0.278, BayesDel 0.260, SpliceAI max delta 0.00) suggest this variant does not have a deleterious effect on protein function or splicing, meeting BP4 at supporting level.
PVS1 is not applicable as this is a missense substitution, not a null variant.
No functional studies, segregation data, de novo observations, case-control data, or pathogenic assertions from reputable sources are available for this variant.
The variant has been reported in ClinVar as Uncertain significance by 5 clinical laboratories (ClinVar Variation ID: 472595), and has been observed once in somatic cancers (COSMIC COSV50100981).
The net evidence profile (PM2_supporting + BP4_supporting) results in an overall classification of Uncertain significance under ACMG/AMP 2015 combination rules.
No criteria match.
Met · 2
PM2 SupportingThis variant is extremely rare in population databases. gnomAD v2.1 reports 1 allele in 31,360 (AF=0.00319%), and gnomAD v4.1 reports 1 allele in 1,612,322 (AF=0.00006%). Both frequencies are well below the 0.1% threshold for PM2. The variant is absent from gnomAD-Canada. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00319% (1/31
- 360)
- homozygous=0
- gnomAD v4.1: AF=0.00006% (1/1
- 612
- 322)
- gnomAD-Canada: absent (0 alleles)
Sources
BP4 SupportingMultiple lines of computational evidence suggest this variant does not impact protein function or splicing. REVEL score of 0.278 is well below the pathogenic threshold of 0.5. BayesDel score of 0.260 is weakly positive. SpliceAI predicts no splicing impact (max delta = 0.00). The weight of in silico evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.278 — below pathogenic threshold of 0.5
- BayesDel: 0.260 — low positive score
- SpliceAI: max delta = 0.00 — no predicted splicing alteration
Sources
Not met · 21 · evaluated, threshold not reached
PVS1 NM_002878.3:c.26G>T is a missense variant (p.Cys9Phe) in exon 1 and does not fall into any PVS1 null-variant category (nonsense, frameshift, or canonical ±1,2 splice consensus). PVS1 is not applicable to missense substitutions. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution (p.Cys9Phe)
- Variant bucket: other — not a null variant
- ClinGen SVI PVS1 framework (PMC6185798) does not apply to missense variants
Sources
PS1 No alternate nucleotide change at position c.26 has been reported as pathogenic in ClinVar or the literature. A pathogenic comparator at the same nucleotide position is required for PS1. Details ▾Hide ▴
PS2 No de novo observations have been reported for this variant. PS2 requires confirmed de novo occurrence with both maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
- ClinVar: 5 clinical laboratory submissions
- none report de novo origin
Still missing
- No trio or parent-of-origin testing data available
Sources
PS3 No variant-specific functional studies have been reported. OncoKB classifies this variant as 'Unknown Oncogenic Effect' with no associated functional evidence. One ClinVar submitter (Color Health) explicitly stated that functional studies have not been reported for this variant. Details ▾Hide ▴
PS4 No case-control studies demonstrate statistically significant enrichment of this variant in affected individuals versus controls. The variant is present in 1 of 31,360 alleles in gnomAD v2.1 and observed only once in somatic COSMIC (COSV50100981, n=1). No published cohort studies report this variant in affected individuals. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/31
- 360 alleles (0.00319%)
- gnomAD v4.1: 1/1
- 612
- 322 alleles (0.00006%)
- COSMIC: 1 somatic observation
- no enrichment data
Still missing
- No published case-control or cohort studies for this variant
Sources
PM1 The variant does not lie within a statistically significant mutational hotspot. Hotspot analysis confirms: 'exact_variant_listed: no' and 'residue_significant: false'. Details ▾Hide ▴
Evidence considered
- Hotspot analysis: variant not in a significant hotspot region
PM6 No de novo observations have been reported for this variant. PM6 requires a de novo observation with confirmed maternity and paternity (without confirmation, this is downgraded to supporting level). Details ▾Hide ▴
Evidence considered
- ClinVar: no submissions report de novo origin
Still missing
- No trio testing or de novo confirmation data
Sources
PP1 No segregation data are available for this variant. PP1 requires co-segregation with disease in multiple affected family members. Details ▾Hide ▴
Still missing
- No family segregation studies available
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.278 (well below the typical pathogenic threshold of 0.5), BayesDel score is 0.260 (low positive), and SpliceAI predicts no splicing impact (max delta score = 0.00). The weight of computational evidence argues against pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.278 (below 0.5 pathogenic threshold)
- BayesDel: 0.260 (weakly positive)
- SpliceAI: max delta = 0.00 (no predicted splicing impact)
Sources
PP4 No specific phenotype or family history data are available for individuals carrying this variant. PP4 requires that the variant has been observed in multiple unrelated patients with a phenotype highly specific for the gene/disease. Details ▾Hide ▴
Evidence considered
- ClinVar: condition labels not provided in submissions
Still missing
- No phenotype data for carriers of this variant
Sources
PP5 No reputable source has classified this variant as pathogenic. All 5 ClinVar clinical laboratory submissions classify this variant as Uncertain significance. The publications cited by submitters (PMID:25741868, PMID:28492532) are general classification methodology papers and do not assert pathogenicity for this specific variant. Details ▾Hide ▴
Evidence considered
- ClinVar: 5/5 submissions classify as Uncertain significance
- No expert panel or reputable source has asserted pathogenicity
Sources
BA1 The maximum allele frequency observed in any population is 0.00649% (gnomAD v2.1, European non-Finnish). This is far below the 1% threshold for BA1. The variant is not common in population databases. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1 max subpopulation AF: 0.00649% (NFE)
- gnomAD v4.1 max subpopulation AF: 8.47e-07 (NFE)
Sources
BS1 The maximum allele frequency observed is 0.00649% (gnomAD v2.1 NFE), well below the 0.3% threshold for BS1. The variant is extremely rare rather than common in the general population. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: AF=0.00319% (overall)
- 0.00649% (NFE subpopulation)
- gnomAD v4.1: AF=0.00006% (overall)
Sources
BS2 The variant has not been observed in a homozygous state in gnomAD (0 homozygotes in both v2.1 and v4.1), and no data exist demonstrating observation in healthy adult controls without disease. BS2 criteria are not satisfied. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 0 homozygotes
- gnomAD v4.1: 0 homozygotes
Still missing
- No data on healthy controls carrying this variant
Sources
BS3 No variant-specific functional studies demonstrating a neutral or benign effect have been reported. OncoKB shows no functional evidence for this variant and classifies its effect as unknown. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no functional evidence
Still missing
- No functional studies demonstrating normal protein function
Sources
BS4 No evidence is available demonstrating lack of segregation with disease in affected families. BS4 requires non-segregation data. Details ▾Hide ▴
Still missing
- No family segregation or non-segregation data
BP1 RAD51D is a gene in which both missense and truncating variants can be pathogenic. BP1 applies to missense variants in genes where only truncating variants are a known disease mechanism, which is not the case for RAD51D. Details ▾Hide ▴
Evidence considered
- RAD51D: both missense and loss-of-function variants are associated with hereditary cancer predisposition
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a known pathogenic RAD51D variant has been reported for a fully penetrant dominant disorder. BP2 requires co-occurrence in trans with a pathogenic variant. Details ▾Hide ▴
Still missing
- No data on co-occurrence with other RAD51D variants
BP5 No alternative molecular basis for disease has been identified in individuals carrying this variant. BP5 requires observation in a case with an alternate molecular cause, which has not been reported. Details ▾Hide ▴
Still missing
- No data on alternate molecular diagnoses in carriers
BP6 No reputable source classifies this variant as benign. All 5 ClinVar submissions classify the variant as Uncertain significance. BP6 requires a reputable source to have classified the variant as benign. Details ▾Hide ▴
Evidence considered
- ClinVar: 5/5 submissions classify as Uncertain significance
- none as benign
Sources
PS5 No reputable source has recently classified this variant as pathogenic. ClinVar lists this variant as Uncertain significance across all 5 clinical laboratory submissions. No expert panel has reviewed this variant. Details ▾Hide ▴
Evidence considered
- ClinVar: 5/5 clinical laboratories classify as Uncertain significance
Sources
Not assessed · 1 · no assessment recorded
PP2 Insufficient gene-level data to determine whether RAD51D has a low rate of benign missense variation and whether missense variants are a common mechanism of disease. Pre-computed missense constraint metrics (e.g., Z-score, missense gnomAD constraint) were not available in the case data. Details ▾Hide ▴
Still missing
- Gene-level missense constraint data not available for RAD51D in this case
Not applicable · 5· recorded as not applicable Show reasons ▾Hide reasons ▴
PM3 N/APM3 is for recessive disorders with a pathogenic variant in trans. RAD51D-associated cancer predisposition is an autosomal dominant condition. Details ▾Hide ▴
No further detail was recorded.
PM4 N/APM4 applies to in-frame insertions/deletions or stop-loss variants. This variant is a missense substitution. Details ▾Hide ▴
No further detail was recorded.
PM5 N/ANo same-residue (Cys9) pathogenic comparator variant was identified to enable PM5 assessment. PM5 candidate harvesting was attempted but returned no eligible comparators. Details ▾Hide ▴
Evidence considered
- PM5 candidate search: no same-residue pathogenic comparators found at Cys9
Sources
pm5_candidates
BP3 N/ABP3 applies to in-frame insertions/deletions in repetitive regions. This variant is a substitution. Details ▾Hide ▴
No further detail was recorded.
BP7 N/ABP7 applies exclusively to synonymous (silent) variants. NM_002878.3:c.26G>T is a missense variant (p.Cys9Phe) and is not eligible for BP7 assessment. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution
- not synonymous
Identifiers
- Gene
- RAD51D
- Transcript
- NM_002878.3
- Coding (HGVS c.)
- NM_002878.3:c.26G>T
- Protein (HGVS p.)
- NP_002869.3:p.(Cys9Phe)
- GRCh38
- chr17:35119588 C>A
- GRCh37
- chr17:33446607 C>A
- ClinVar
- 472595
- COSMIC
- COSV50100981
Gene diagram
Every interpreted variant in RAD51D, mapped onto the exon structure of NM_002878.3. Select a row to find it on the plot.
RAD51DNM_002878.3
Fetching transcript structure from UCSC…
Exons
—
Transcript span
—
Strand
—
Variants mapped
—
Source
UCSC ncbiRefSeqCurated
All variants in RAD51D
—
Select a row to find it on the plot; use the link to open its page.
| Protein | Location | Classification | Link |
|---|
gnomAD v4.1
1 / 1,612,322 alleles
AF 6.2e-07 · 0 homozygotes
gnomAD v2.1
1 / 31,360 alleles
AF 3.19e-05 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 6.2e-07 · 1 / 1,612,322 alleles · 0 hom
| European (non-Finnish)1 / 1,179,954 | 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.
gnomAD v2.1
AF 3.2e-05 · 1 / 31,360 alleles · 0 hom
| European (non-Finnish)1 / 15,404 | 6.5e-05 |
0 alternate alleles recorded in 7 other groups: African/African American, Admixed American, Ashkenazi Jewish, East Asian, European (Finnish), Remaining individuals, South Asian.
Statements
gnomAD v4.1
This variant is present in gnomAD v4.1 (AF= 6.20224e-07; MAF= 0.00006%, 1/1612322 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47491e-07; MAF= 0.00008%, 1/1179954 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18878e-05; MAF= 0.00319%, 1/31360 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.49182e-05; MAF= 0.00649%, 1/15404 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.278
- BayesDel
- 0.260
How the predictions were used
BP4 SupportingMultiple lines of computational evidence suggest this variant does not impact protein function or splicing. REVEL score of 0.278 is well below the pathogenic threshold of 0.5. BayesDel score of 0.260 is weakly positive. SpliceAI predicts no splicing impact (max delta = 0.00). The weight of in silico evidence supports a benign interpretation. Details ▾Hide ▴
Evidence considered
- REVEL: 0.278 — below pathogenic threshold of 0.5
- BayesDel: 0.260 — low positive score
- SpliceAI: max delta = 0.00 — no predicted splicing alteration
Sources
PP3 Multiple in silico predictors do not support a deleterious effect. REVEL score is 0.278 (well below the typical pathogenic threshold of 0.5), BayesDel score is 0.260 (low positive), and SpliceAI predicts no splicing impact (max delta score = 0.00). The weight of computational evidence argues against pathogenicity. Details ▾Hide ▴
Evidence considered
- REVEL: 0.278 (below 0.5 pathogenic threshold)
- BayesDel: 0.260 (weakly positive)
- SpliceAI: max delta = 0.00 (no predicted splicing impact)
Sources
BP7 N/ABP7 applies exclusively to synonymous (silent) variants. NM_002878.3:c.26G>T is a missense variant (p.Cys9Phe) and is not eligible for BP7 assessment. Details ▾Hide ▴
Evidence considered
- Variant class: missense substitution
- not synonymous
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.278. BayesDel score = 0.260344.
2 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata. None of the listed paper records explicitly indicates that the variant is named.
Recorded publications
-
PMID 25741868 ↗Standards and guidelines for the interpretation of sequence variants: a joint consensus recommendation of the American College of Medical Genetics and Genomics and the Association for Molecular Pathology.Richards S et al. · 2015This is the ACMG/AMP standards and guidelines for sequence variant interpretation (Richards et al., 2015). It describes the general classification framework and criteria weighting rules. NM_002878.3:c.26G>T and p.Cys9Phe are not mentioned in this paper.Does not name this variant
-
PMID 25394175 ↗A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment.Hampel H et al. · 2015This is a practice guideline from ACMG and NSGC on referral indications for cancer predisposition assessment (Hampel et al., 2015). It provides criteria for when to refer patients for cancer genetic consultation. NM_002878.3:c.26G>T and p.Cys9Phe are not mentioned in this paper.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
1 / 1,612,322 recorded alleles
Open source ↗
gnomAD v2.1
Captured gnomAD v2.1 source record
Open source ↗
SpliceAI Lookup
Recorded maximum delta 0.000
Open source ↗
ClinVar
5 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/472595/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-33446607-C-A?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-35119588-C-A?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-35119588-C-A
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002878.3%3Ac.26G%…
- OncoKB ↗www.oncokb.org/gene/RAD51D/C9F
- COSMIC ↗cancer.sanger.ac.uk/cosmic/mutation/overview?id=208548016
- 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= 6.20224e-07; MAF= 0.00006%, 1/1612322 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.47491e-07; MAF= 0.00008%, 1/1179954 alleles, homozygotes = 0).
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.18878e-05; MAF= 0.00319%, 1/31360 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 6.49182e-05; MAF= 0.00649%, 1/15404 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (5 clinical laboratories). (ClinVarID = 472595)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.278. BayesDel score = 0.260344.
Functional
OncoKB did not identify variant-specific reviewed functional evidence for this variant; gene-level curated context is available for reviewer follow-up. RAD51D, a DNA repair protein, is infrequently altered in cancer.
Somatic
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV50100981, n = 1 times).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.