About RAD51D
No gene-level summary was recorded for this case.
Previous versions
Variant interpretation report
RAD51D c.829C>G, p.(Leu277Val)
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_002878.4:c.829C>G is absent or present at extremely low frequency in population databases. gnomAD v2.1: 1/251,446 alleles (AF = 0.00040%). gnomAD v4.1: 6/1,614,064 alleles (AF = 0.00037%). Both are well below the 0.1% threshold for PM2 application. No homozygotes observed.
Benign criteria applied · 1
BP4Supporting
BP4 · supporting
Multiple independent lines of computational evidence suggest this variant has no deleterious impact on the gene product. REVEL score 0.131 (well below the 0.5 pathogenic threshold, consistent with tolerated prediction). BayesDel score -0.327 (negative, predicting benign effect). SpliceAI max delta 0.00 (no predicted impact on splicing). Three orthogonal in silico approaches converge on a benign or neutral prediction.
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
6 / 1,614,064 alleles
gnomAD v4.1: 6 / 1,614,064 alleles. Recorded AF 3.71732e-06. Recorded homozygote count 0.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.977e-06; MAF= 0.00040%, 1/251446 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.7926e-06; MAF= 0.00088%, 1/113732 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
3 reported laboratory submissions
3 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
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: 2 met · 22 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
NM_002878.4:c.829C>G (p.Leu277Val) is a missense variant in RAD51D, a moderate-penetrance hereditary breast and ovarian cancer predisposition gene involved in homologous recombination repair.
This variant is present at extremely low frequency in population databases: gnomAD v2.1 AF = 0.00040% (1/251,446 alleles) and gnomAD v4.1 AF = 0.00037% (6/1,614,064 alleles), meeting PM2 at supporting strength.
Multiple in silico predictors consistently indicate a tolerated or benign effect: REVEL score 0.131, BayesDel score -0.327, and SpliceAI max delta 0.00. These independent computational lines of evidence support BP4 at supporting strength.
No functional studies, case-control data, family segregation analysis, de novo reports, or variant-specific publications were identified for this variant. ClinVar reports Uncertain significance (3 clinical laboratories, 1-star review). OncoKB reports unknown oncogenic effect.
Applying generic ACMG/AMP 2015 combination rules: PM2 (supporting) + BP4 (supporting) yields an overall classification of Uncertain Significance (VUS), consistent with the ClinVar consensus.
No criteria match.
Met · 2
PM2 SupportingNM_002878.4:c.829C>G is absent or present at extremely low frequency in population databases. gnomAD v2.1: 1/251,446 alleles (AF = 0.00040%). gnomAD v4.1: 6/1,614,064 alleles (AF = 0.00037%). Both are well below the 0.1% threshold for PM2 application. No homozygotes observed. Details ▾Hide ▴
Evidence considered
- gnomAD v2.1: 1/251
- 446 alleles (AF = 3.977e-06)
- no homozygotes.
- gnomAD v4.1: 6/1
- 614
- 064 alleles (AF = 3.717e-06)
- no homozygotes
- grpmax FAF = 1.83e-06.
Sources
BP4 SupportingMultiple independent lines of computational evidence suggest this variant has no deleterious impact on the gene product. REVEL score 0.131 (well below the 0.5 pathogenic threshold, consistent with tolerated prediction). BayesDel score -0.327 (negative, predicting benign effect). SpliceAI max delta 0.00 (no predicted impact on splicing). Three orthogonal in silico approaches converge on a benign or neutral prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.131 (tolerated/benign).
- BayesDel: -0.326833 (benign prediction).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
Not met · 22 · evaluated, threshold not reached
PS1 No pathogenic variant causing the same amino acid change (p.Leu277Val) via a different nucleotide change has been identified in ClinVar or the literature. PS1 requires a previously established pathogenic variant at the same residue with the same amino acid alteration. Details ▾Hide ▴
Evidence considered
- No alternative nucleotide change producing p.Leu277Val found in ClinVar variation records.
Sources
PS2 No de novo occurrence data are available for this variant. PS2 requires confirmation that both parents are negative for the variant with parental identity confirmed. Details ▾Hide ▴
Evidence considered
- No de novo reports identified in ClinVar submissions or literature.
Still missing
- No parental testing data available.
PS3 No variant-specific functional studies have been reported for NM_002878.4:c.829C>G (p.Leu277Val). OncoKB reports unknown oncogenic effect with no curated functional evidence. The Color Health ClinVar submission explicitly states that functional studies have not been reported for this variant. No publications with experimental functional characterization of this variant or a systematically characterized range encompassing position 277 were identified. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
- ClinVar SCV001340964 (Color Health): 'functional studies have not been reported for this variant'.
Still missing
- No functional studies available for this variant or a systematically characterized range including position 277.
Sources
PS4 No case-control or cohort data demonstrating enrichment of this variant in affected individuals versus controls are available. The variant has been observed in gnomAD at extremely low frequency but no disease-specific prevalence comparison exists. Details ▾Hide ▴
Evidence considered
- No case-control or cohort studies reporting this variant identified.
Still missing
- No affected vs. control prevalence data for this variant.
PM1 Position 277 in RAD51D does not lie within a statistically significant mutational hotspot (cancerhotspots.org negative). While RAD51D contains a RecA-like ATPase domain, there is no evidence that position 277 resides in a well-characterized critical functional domain where missense variants are established as pathogenic. Without a VCEP-defined domain map or literature establishing this specific residue as functionally critical, PM1 cannot be applied at the generic ACMG level. Details ▾Hide ▴
Evidence considered
- CancerHotspots.org: no significant hotspot at this residue.
- No VCEP or literature-defined critical domain map placing position 277 in a missense-enriched functional domain.
Still missing
- No RAD51D-specific domain-level PM1 framework available.
PM5 PM5 candidate harvesting did not identify any same-residue pathogenic comparator variants at position 277 in RAD51D. No ClinVar entry reports a different missense change at p.Leu277 classified as pathogenic. PM5 requires that a different pathogenic missense variant exists at the same amino acid residue. Details ▾Hide ▴
Evidence considered
- PM5 candidate search found 0 same-residue candidates
- no pathogenic comparators at p.Leu277.
Sources
pm5_candidates
PM6 No de novo occurrence of this variant has been reported. PM6 requires confirmation of de novo status with maternity and paternity confirmed. Details ▾Hide ▴
Evidence considered
- No de novo reports for this variant in ClinVar or literature.
Still missing
- No de novo testing data.
PP1 No cosegregation data are available for this variant. PP1 requires observation of the variant cosegregating with disease in multiple affected family members. Details ▾Hide ▴
Evidence considered
- No family segregation studies available.
Still missing
- No family studies or segregation data.
PP2 PP2 requires a gene with a low rate of benign missense variation where missense variants are a common mechanism of disease. While RAD51D loss-of-function is an established disease mechanism for hereditary breast and ovarian cancer, the HCI prior is not available for this gene, and there is insufficient evidence to establish that missense variants specifically are the predominant disease mechanism. RAD51D-associated cancer risk involves both truncating and missense variants. Details ▾Hide ▴
Evidence considered
- RAD51D LoF is an established disease mechanism
- but without HCI prior or missense constraint data
- PP2 cannot be confidently applied.
Still missing
- No HCI prior score for RAD51D
- insufficient data on benign missense constraint.
Sources
pvs1_gene_context
PP3 Multiple lines of computational evidence suggest this variant is tolerated, not deleterious. REVEL score 0.131 (<0.5 threshold), BayesDel score -0.327 (negative, benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). All available in silico predictors agree on a benign or neutral effect, which contradicts PP3 application. Details ▾Hide ▴
Evidence considered
- REVEL: 0.131 (benign-leaning
- below typical 0.5 pathogenic threshold).
- BayesDel: -0.326833 (negative score
- benign prediction).
- SpliceAI: max delta 0.00 (no splice alteration predicted).
Sources
PP4 No patient phenotype or family history data are provided in the case materials. PP4 requires that the patient's phenotype or family history is highly specific for a disease with a single genetic etiology. Details ▾Hide ▴
Evidence considered
- No phenotype or family history data available for this case.
Still missing
- Patient phenotype and family history not provided.
PP5 ClinVar classification for this variant is Uncertain significance (Variation ID 539856), with review status 'criteria provided, single submitter' (1-star). PP5 requires a reputable source to have reported the variant as pathogenic. A 3-star expert panel classification is required for PP5 at supporting strength; this variant has no expert panel review and is classified as VUS by all submitters. Details ▾Hide ▴
Evidence considered
- ClinVar: VUS
- 1-star review (criteria provided
- single submitter)
- 3 clinical laboratories
- no expert panel.
- No submitter classifies this variant as pathogenic.
Sources
BA1 The variant is extremely rare in population databases. gnomAD v2.1 AF = 0.00040% and v4.1 AF = 0.00037%, both far below the BA1 threshold of >1%. BA1 is not applicable. Details ▾Hide ▴
BS1 The variant allele frequency (gnomAD ~0.0004%) is far below the BS1 threshold of >0.3% for a dominant disorder. BS1 is not met. Details ▾Hide ▴
Evidence considered
- gnomAD AF ~0.0004%
- well below BS1 threshold of >0.3%.
Sources
BS2 No data are available demonstrating observation of this variant in healthy adults at an age when the disease would be expected to have manifested with full penetrance. BS2 requires documented observation in a healthy adult control for a disorder with full penetrance expected at an early age. Details ▾Hide ▴
Evidence considered
- No healthy adult control data available for this variant.
Still missing
- No healthy adult control observations documented.
BS3 No well-established functional studies demonstrate that this variant has no damaging effect on protein function or splicing. OncoKB reports unknown oncogenic effect with no curated functional evidence. No publications with experimental characterization of this variant were identified. Details ▾Hide ▴
Evidence considered
- OncoKB: Unknown Oncogenic Effect
- no variant-specific functional evidence.
- No published functional studies for this variant identified.
Still missing
- No functional studies available to demonstrate benign effect.
Sources
BS4 No family segregation data are available to demonstrate lack of cosegregation with disease. BS4 requires observation that the variant does not segregate with disease in affected family members. Details ▾Hide ▴
Evidence considered
- No family studies or segregation data available.
Still missing
- No segregation data.
BP1 BP1 applies when a missense variant occurs in a gene for which primarily truncating variants are known to cause disease. RAD51D-associated hereditary cancer predisposition involves both truncating and missense pathogenic variants. The ACMG clinical practice resource (PMID:41070818) describes RAD51D GPVs broadly without distinguishing variant types as the sole disease mechanism. BP1 is not appropriate for a gene where missense variants are also an established pathogenic mechanism. Details ▾Hide ▴
Evidence considered
- RAD51D pathogenic variants include both truncating and missense
- not a gene where only truncating variants cause disease.
Sources
pvs1_gene_context
BP2 No observation of this variant in trans with a known pathogenic variant in RAD51D has been reported. BP2 requires documented observation in trans with a pathogenic variant for a fully penetrant dominant disorder. Details ▾Hide ▴
Evidence considered
- No in trans observations documented.
Still missing
- No phasing or in trans data.
BP5 No data are available showing this variant in a case with an alternative molecular basis for disease. BP5 requires a documented alternate genetic cause explaining the phenotype in a proband who also carries this variant. Details ▾Hide ▴
Evidence considered
- No cases with alternative molecular diagnosis reported.
Still missing
- No alternate molecular basis data.
BP6 ClinVar classification for this variant is Uncertain significance, not benign. No reputable source has reported the variant as benign. BP6 requires a 3-star expert panel classification of benign/likely benign; this variant has only 1-star review status and is classified as VUS. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 539856: VUS
- 1-star review
- not reported as benign by any submitter.
Sources
PS5 No reputable source has reported this variant as pathogenic. ClinVar classification is Uncertain significance across all three clinical laboratory submissions. Details ▾Hide ▴
Evidence considered
- ClinVar Variation ID 539856: Uncertain significance
- 3 clinical laboratories
- review status 'criteria provided
- single submitter'.
Sources
Not applicable · 2· recorded as not applicable Show reasons ▾Hide reasons ▴
PVS1 N/ANM_002878.4:c.829C>G is a missense variant (p.Leu277Val). It does not fall into the generic PVS1 null-variant buckets of nonsense, frameshift, or canonical ±1,2 splice consensus variants per ClinGen SVI PVS1 recommendations (PMC6185798). Details ▾Hide ▴
Evidence considered
- Variant is missense
- not null-variant
- PVS1 framework does not apply.
Sources
pvs1_generic_framework ↗pvs1_variant_assessment
BP7 N/ABP7 applies exclusively to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. NM_002878.4:c.829C>G is a missense variant (p.Leu277Val), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Leu277Val)
- not synonymous. BP7 does not apply.
Identifiers
- Gene
- RAD51D
- Transcript
- NM_002878.4
- Coding (HGVS c.)
- NM_002878.4:c.829C>G
- Protein (HGVS p.)
- NP_002869.3:p.(Leu277Val)
- GRCh38
- chr17:35101275 G>C
- GRCh37
- chr17:33428294 G>C
- ClinVar
- 539856
Gene diagram
Every interpreted variant in RAD51D, mapped onto the exon structure of NM_002878.4. Select a row to find it on the plot.
RAD51DNM_002878.4
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
6 / 1,614,064 alleles
AF 3.72e-06 · 0 homozygotes · FAF 1.83e-06
gnomAD v2.1
1 / 251,446 alleles
AF 3.98e-06 · 0 homozygotes
gnomAD-Canada v1.0
Allele count data not recorded
By genetic ancestry
gnomAD v4.1
AF 3.7e-06 · 6 / 1,614,064 alleles · 0 hom · FAF 1.8e-06
| European (non-Finnish)6 / 1,180,042 | 5.1e-06 |
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 4e-06 · 1 / 251,446 alleles · 0 hom
| European (non-Finnish)1 / 113,732 | 8.8e-06 |
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= 3.71732e-06; MAF= 0.00037%, 6/1614064 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08456e-06; MAF= 0.00051%, 6/1180042 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.977e-06; MAF= 0.00040%, 1/251446 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.7926e-06; MAF= 0.00088%, 1/113732 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
SpliceAI and Pangolin
Other predictors
- REVEL
- 0.131
- BayesDel
- -0.327
How the predictions were used
BP4 SupportingMultiple independent lines of computational evidence suggest this variant has no deleterious impact on the gene product. REVEL score 0.131 (well below the 0.5 pathogenic threshold, consistent with tolerated prediction). BayesDel score -0.327 (negative, predicting benign effect). SpliceAI max delta 0.00 (no predicted impact on splicing). Three orthogonal in silico approaches converge on a benign or neutral prediction. Details ▾Hide ▴
Evidence considered
- REVEL: 0.131 (tolerated/benign).
- BayesDel: -0.326833 (benign prediction).
- SpliceAI: max delta 0.00 (no splice impact).
Sources
PP3 Multiple lines of computational evidence suggest this variant is tolerated, not deleterious. REVEL score 0.131 (<0.5 threshold), BayesDel score -0.327 (negative, benign-leaning), and SpliceAI max delta score 0.00 (no predicted splice impact). All available in silico predictors agree on a benign or neutral effect, which contradicts PP3 application. Details ▾Hide ▴
Evidence considered
- REVEL: 0.131 (benign-leaning
- below typical 0.5 pathogenic threshold).
- BayesDel: -0.326833 (negative score
- benign prediction).
- SpliceAI: max delta 0.00 (no splice alteration predicted).
Sources
BP7 N/ABP7 applies exclusively to synonymous (silent) variants for which splicing prediction algorithms predict no impact on the splice consensus sequence. NM_002878.4:c.829C>G is a missense variant (p.Leu277Val), not a synonymous variant. Details ▾Hide ▴
Evidence considered
- Variant is missense (p.Leu277Val)
- not synonymous. BP7 does not apply.
Statement
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.131. BayesDel score = -0.326833.
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. · 2015Standards 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 (ACMG/AMP 2015). This is a methodological framework paper describing variant classification criteria and rules; it does not report or evaluate any specific variant.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. · 2015A practice guideline from the American College of Medical Genetics and Genomics and the National Society of Genetic Counselors: referral indications for cancer predisposition assessment. This is a clinical practice guideline for referral indications in cancer genetics; it does not report or evaluate any specific variant.Does not name this variant
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
gnomAD v4.1
6 / 1,614,064 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
3 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/539856/
- gnomAD v2.1 ↗gnomad.broadinstitute.org/variant/17-33428294-G-C?dataset=gnomad_r2_1
- gnomAD v4.1 ↗gnomad.broadinstitute.org/variant/chr17-35101275-G-C?dataset=gn…
- gnomAD-Canada ↗http://192.168.4.76:8001/variant/17-35101275-G-C
- SpliceAI Lookup ↗spliceailookup.broadinstitute.org/#variant=NM_002878.4%3Ac.829C…
- OncoKB ↗www.oncokb.org/gene/RAD51D/L277V
- COSMIC ↗cancer.sanger.ac.uk/cosmic/search?q=RAD51D+c.829C%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
This variant is present in gnomAD v4.1 (AF= 3.71732e-06; MAF= 0.00037%, 6/1614064 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 5.08456e-06; MAF= 0.00051%, 6/1180042 alleles, homozygotes = 0); grpmax FAF= 1.83e-06.
gnomAD v2.1
This variant is present in gnomAD v2.1 (AF= 3.977e-06; MAF= 0.00040%, 1/251446 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.7926e-06; MAF= 0.00088%, 1/113732 alleles, homozygotes = 0).
gnomAD-Canada
Absent from gnomAD-Canada v1.0.
ClinVar
This variant has been reported in ClinVar as Uncertain significance (3 clinical laboratories). (ClinVarID = 539856)
In silico
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.00). REVEL score = 0.131. BayesDel score = -0.326833.
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 not previously been reported in somatic cancers (COSMIC).
Cancer Hotspots
This variant does not lie in a statistically significant hotspot.