No variant summary was recorded for this case.
Five-step scale from benign to pathogenic. This variant is likely pathogenic. Select a step to read what it means.
Likely pathogenic.A likely pathogenic classification under the recorded framework.
Gene-level background from the recorded interpretation.
Words with a dotted underline have a short definition. Hover or tap them.RAD51D encodes a protein that works with other DNA-repair proteins to help accurately repair broken DNA through homologous recombination. Inherited changes in RAD51D increase the risk of ovarian cancer and may also increase breast cancer risk. RAD51D acts as a tumor-suppressor gene, and changes in it can contribute to chromosome instability and, rarely, resistance to chemotherapy in cancer cells.
The recorded framework is Not recorded. The criteria and strengths shown below come from the saved assessment; this page does not recalculate the classification.
The applied criteria and their strengths are shown as assessed under the stated framework.
Met at very strong: c.694C>T creates p.Arg232Ter in exon 8 of 10, predicting nonsense-mediated decay and loss of 98 of 329 amino acids.
Met at supporting: gnomAD maximum observed allele frequency 3.21e-05 is below the PM2 threshold of <=0.0001, with zero homozygotes.
No benign criterion marked as applied in the recorded assessment.
Likely Pathogenic: PVS1 (very strong) plus PM2 (supporting) satisfy the generic ACMG/AMP fallback rule for one very strong and one supporting criterion.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 19 / 1,611,726 alleles. Recorded AF 1.17886e-05. Recorded homozygote count 0.
This variant is present in gnomAD v2.1 (AF= 1.44288e-05; MAF= 0.00144%, 4/277224 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.16011e-05; MAF= 0.00316%, 4/126578 alleles, homozygotes = 0); grpmax FAF= 7.17e-06.
Not available in gnomAD-Canada v1.0.
No SpliceAI or REVEL score is recorded in the fields used for this tile.
28 Pathogenic · 1 pathogenic · 1 Likely pathogenic. ClinVar API review status: criteria provided, multiple submitters, no conflicts.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Not recorded, with the data and sources behind each one.
28 criteria with recorded statuses: 2 met · 5 not met · 11 not assessed · 10 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No ClinGen RAD51D-specific VCEP specification is available, so generic ACMG/AMP criteria were used.
The exact variant has a published carrier observation, but the available evidence contains no proband-parent testing, assumed de novo pedigree, informative segregation, or non-segregation data.
No RAD51D-specific VCEP or gene framework was available, so generic ACMG/AMP criteria rules were used.
PS4 was not assessed because exact-variant evidence consisted of one reported carrier without a variant-specific case-control enrichment statistic.
PP4 was not assessed because the patient's detailed phenotype and family history were not available.
PP5 and BP6 were not triggered because ClinVar showed zero expert-panel submissions for the exact variant.
BP5 was not assessed because no alternative molecular diagnosis explaining the phenotype was documented.
Population evidence supports PM2 at supporting strength because the maximum observed gnomAD subpopulation AF is 3.21e-05, below 0.0001, with no homozygotes.
BA1 and BS1 are not met because the observed frequencies are far below 0.05 and 0.01, respectively.
BS2 is not met because no homozygotes or other healthy-individual observations inconsistent with disease are reported.
No criteria match.
PVS1 is met at full strength under the generic ClinGen SVI framework (PMC6185798). NM_002878.4:c.694C>T is a nonsense variant producing NP_002869.3:p.(Arg232Ter) in the MANE Select RAD51D transcript (transcript variant 1). Variant Validator places it in exon 8 of 10, with downstream exons 9 and 10; the premature stop is therefore well upstream of the final exon junction and is expected to trigger nonsense-mediated decay rather than escape it. The predicted product retains 232 of the 329 reference amino acids and loses the C-terminal 98 amino acids, while the gene-level evidence supports RAD51D loss of function as a disease mechanism. No applicable RAD51D-specific VCEP/CSPEC rule, non-critical-exon exception, repeat-region concern, or population LoF-enrichment downgrade was identified. Because no named downgrade rule applies, the correct PVS1 strength is literal "very strong".
Generic ClinGen SVI PVS1 framework, PMC6185798; full-strength nonsense variant with predicted NMD and no applicable downgrade
No applicable RAD51D-specific VCEP or gene framework was identified, so the supplied generic SVI PM2 threshold applies. The variant is rare but observed in both default all-comers datasets: AF 1.4428765e-05 in gnomAD v2.1 (4/277224 alleles; 0 homozygotes) and AF 1.1788604e-05 in gnomAD v4.1 (19/1611726 alleles; 0 homozygotes). The highest reported subpopulation AFs, 3.1601068e-05 in v2.1 and 3.2051282e-05 in v4.1, remain below the PM2 supporting threshold of <=0.0001. PM2 is therefore met at supporting strength. The available non-cancer v2.1 exome subset is not substituted because no governing specification requires it; the default all-comers totals control.
{'source': 'generic ClinGen SVI recommendation', 'threshold': '<=0.0001', 'metric': 'maximum credible allele frequency', 'strength': 'supporting'}
PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar identifies the exact variant NM_002878.4:c.694C>T (p.Arg232Ter), but the record has no expert-panel submissions and is supported only by single-submitter or aggregate laboratory assertions; the recorded review status is criteria provided, single submitter, with zero expert-panel submissions. These assertions must not trigger PP5.
PP5 applies only when an exact-variant ClinVar expert panel classifies the variant as Pathogenic or Likely pathogenic; laboratory submissions and aggregate labels are excluded.
No applicable RAD51D-specific VCEP or gene framework was identified, so the generic ACMG/AMP threshold applies. The variant's all-comers gnomAD allele frequencies are 1.4428765e-05 (4/277224 alleles) in gnomAD v2.1 and 1.1788604e-05 (19/1611726 alleles) in gnomAD v4.1; the highest reported subpopulation frequencies are 3.1601068e-05 and 3.2051282e-05, respectively. These values are far below the BA1 stand-alone threshold of >=0.05, so BA1 is not met. The available non-cancer v2.1 exome subset is not substituted because no governing specification requires that source; the default all-comers totals therefore control.
{'source': 'generic ACMG/AMP', 'threshold': '>=0.05', 'metric': 'maximum credible allele frequency'}
No applicable RAD51D-specific VCEP or gene framework was identified, so the supplied generic SVI BS1 threshold applies. The all-comers gnomAD AF is 1.4428765e-05 in v2.1 and 1.1788604e-05 in v4.1, with highest subpopulation AFs of 3.1601068e-05 and 3.2051282e-05. All are below the generic BS1 threshold of >=0.01, so the observed population frequency does not support BS1. The available non-cancer v2.1 exome subset is not substituted because no governing specification requires that source; the default all-comers totals control.
{'source': 'generic SVI default', 'threshold': '>=0.01', 'metric': 'maximum credible allele frequency'}
The available population datasets show no homozygotes for this variant: gnomAD v2.1 reports 0 homozygotes among 277224 alleles and gnomAD v4.1 reports 0 among 1611726 alleles, with no homozygotes in the reported subpopulations. Therefore the population evidence does not meet BS2, which requires the variant to be observed in healthy individuals in a manner inconsistent with disease, and no BS2 support is assigned.
{'source': 'generic ACMG/AMP', 'requirement': 'observation in healthy individuals, typically including unaffected homozygotes, inconsistent with disease'}
BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar identifies the exact variant NM_002878.4:c.694C>T (p.Arg232Ter), but the record has no expert-panel submissions and contains Pathogenic or Likely pathogenic laboratory assertions rather than an expert-panel Benign or Likely benign classification. Therefore BP6 is not met.
BP6 applies only when an exact-variant ClinVar expert panel classifies the variant as Benign or Likely benign; laboratory submissions and aggregate labels are excluded.
No case-level evidence documents the variant in a proband with confirmed absence in both unaffected biological parents, and the published exact-variant report provides no parental-testing or de novo information.
Generic ACMG/AMP PS2 requires a confirmed de novo variant in a patient with a phenotype consistent with the gene-associated disorder and confirmed parentage; this evidence is absent.
PS3 cannot be applied because no validated, variant-specific functional assay for NM_002878.4:c.694C>T (NP_002869.3:p.(Arg232Ter)) was identified. PMID:21822267 reports homologous-recombination and olaparib-sensitivity experiments involving RAD51D loss of function, but the target variant was not tested; PMID:22986143 likewise reports loss-of-function RAD51D variants and referenced PARP-inhibitor sensitivity without testing p.Arg232Ter. The exact-variant report in PMID:27083178 is a sequencing case observation and provides no functional assay. Therefore, the available evidence does not establish a PS3 functional result or permit strength calibration.
Generic ACMG PS4 requires statistically significant enrichment of the variant in affected individuals versus appropriate controls, or a sufficiently documented variant-specific case series. The exact variant NM_002878.4:c.694C>T (p.Arg232Ter) is reported in one patient in a prospective triple-negative breast cancer cohort (1 of 105 tested patients), but the paper provides no matched control comparison, odds ratio, P value for this exact variant, or case-series count adequate for PS4. Gene-level RAD51D enrichment reported for other truncating variants cannot be transferred to this exact variant. Therefore PS4 cannot be assessed.
Generic ACMG/AMP PS4: prevalence of the variant in affected individuals is significantly increased compared with controls; variant-specific enrichment evidence is required.
No applicable RAD51D-specific VCEP framework was available, so generic ACMG/AMP reasoning applies. PM3 requires an affected individual with the variant in trans with a pathogenic or likely pathogenic variant in a gene established for autosomal-recessive disease. The available evidence reports RAD51D c.694C>T (p.Arg232*) in one affected individual but provides no second RAD51D variant, phase, biallelic state, or validated autosomal-recessive RAD51D phenotype; therefore PM3 cannot be assessed from the available evidence.
The exact variant is reported in a patient, but there is no evidence that it was assumed de novo without parental confirmation; neither parental testing nor a documented compatible phenotype and pedigree are available.
Generic ACMG/AMP PM6 may be considered for a presumed de novo variant when parental testing is unavailable, but a compatible phenotype and credible case-level de novo context are still required; those data are absent.
No informative meioses, affected relatives, co-segregation counts, likelihood analysis, or variant-specific family pedigree is reported for NM_002878.4:c.694C>T; the available publications discuss other RAD51D variants or unrelated carriers.
Generic ACMG/AMP PP1 requires co-segregation of the variant with disease in multiple affected family members; strength depends on the number and informativeness of meioses or an accepted statistical analysis.
Generic PP4 requires the patient's phenotype or family history to be highly specific for a disease associated with the gene. The available exact-variant report identifies a triple-negative breast cancer cohort and states that the tumor intrinsic subtype was not analyzed for the carrier, but it does not provide a complete individual phenotype, family history, or a sufficiently specific clinical presentation for this case. A gene-level cancer association or an exact-variant pathogenic label is not a substitute for the patient's phenotype. PP4 cannot be assessed from the available evidence.
Generic ACMG/AMP PP4: the patient's phenotype or family history is highly specific for a disease with a single-gene etiology.
BS3 cannot be applied because no validated, variant-specific benign functional assay for NM_002878.4:c.694C>T (NP_002869.3:p.(Arg232Ter)) was identified. The available functional literature concerns RAD51D loss of function or other variants and does not demonstrate preserved function for p.Arg232Ter. PMID:27083178 reports the exact variant as a sequencing finding but contains no functional assay. Consequently, there is no assay result with suitable controls and biological relevance supporting benign functional evidence or a BS3 strength level.
No tested unaffected relatives carrying the variant, no non-segregation pedigree, and no reliable phenotype-negative family analysis are documented; therefore the available evidence cannot support or refute non-segregation.
Generic ACMG/AMP BS4 requires absence of segregation in affected family members, or the presence of the variant in appropriately informative unaffected relatives, while accounting for age-related penetrance and phenocopies; these data are absent.
No applicable RAD51D-specific VCEP framework was available, so generic ACMG/AMP reasoning applies. BP2 requires observation of the variant in trans with a pathogenic or likely pathogenic variant for an autosomal-dominant disorder, or in cis with a pathogenic variant for an autosomal-recessive disorder. The available report of RAD51D c.694C>T (p.Arg232*) contains no second variant or phase information, and no validated allelic observation establishes either configuration; therefore BP2 cannot be assessed.
No applicable RAD51D-specific BP5 specification was available, so the generic ACMG/AMP definition applies: the patient has a molecular diagnosis at another locus that explains the phenotype, making this variant unlikely to be causal. The evidence reviewed contains no confirmed alternative molecular diagnosis for the relevant patient and no BP5 likelihood-ratio-style measurement or governing threshold. BP5 cannot be assessed.
Generic ACMG/AMP BP5: a molecular diagnosis at another locus explains the phenotype; no applicable RAD51D-specific numeric BP5 rule was available.
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_missense
PP3 is not applicable because NM_002878.4:c.694C>T is a nonsense variant producing p.(Arg232Ter), a protein-length-changing truncating consequence outside the calibrated computational-evidence scope. Per the governing generic ACMG framework, SpliceAI, REVEL, and BayesDel must not be evaluated for this out-of-scope criterion.
deterministic_prefilter: requires_missense
deterministic_prefilter: requires_repeat_region_indel
BP4 is not applicable because NM_002878.4:c.694C>T is a nonsense variant producing p.(Arg232Ter), a protein-length-changing truncating consequence outside the calibrated computational-evidence scope. Per the governing generic ACMG framework, SpliceAI, REVEL, and BayesDel must not be evaluated for this out-of-scope criterion.
deterministic_prefilter: requires_synonymous
Every interpreted variant in RAD51D, mapped onto the exon structure of NM_002878.4. Select a row to find it on the plot.
| Protein | Location | Classification | Link |
|---|
| Remaining individuals2 / 62,400 | 3.2e-05 |
| Admixed American1 / 59,602 | 1.7e-05 |
| African/African American1 / 74,888 | 1.3e-05 |
| European (non-Finnish)15 / 1,179,156 | 1.3e-05 |
| European (non-Finnish)4 / 126,578 | 3.2e-05 |
This variant is present in gnomAD v4.1 (AF= 1.17886e-05; MAF= 0.00118%, 19/1611726 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20513e-05; MAF= 0.00321%, 2/62400 alleles, homozygotes = 0); grpmax FAF= 7.64e-06.
This variant is present in gnomAD v2.1 (AF= 1.44288e-05; MAF= 0.00144%, 4/277224 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.16011e-05; MAF= 0.00316%, 4/126578 alleles, homozygotes = 0); grpmax FAF= 7.17e-06.
Not available in gnomAD-Canada v1.0.
PP3 is not applicable because NM_002878.4:c.694C>T is a nonsense variant producing p.(Arg232Ter), a protein-length-changing truncating consequence outside the calibrated computational-evidence scope. Per the governing generic ACMG framework, SpliceAI, REVEL, and BayesDel must not be evaluated for this out-of-scope criterion.
BP4 is not applicable because NM_002878.4:c.694C>T is a nonsense variant producing p.(Arg232Ter), a protein-length-changing truncating consequence outside the calibrated computational-evidence scope. Per the governing generic ACMG framework, SpliceAI, REVEL, and BayesDel must not be evaluated for this out-of-scope criterion.
deterministic_prefilter: requires_synonymous
SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. BayesDel score = 0.63.
6 paper records listed. 2 cited in the classification.
All the mutations are predicted to result in protein truncation through frameshifting insertions or deletions (n=3), the generation of nonsense codons (n=4) or splice defects (n=2) (Table 1 and Supplementary Table 4).
Location Results, mutation analysis paragraph; Drug sensitivity paragraph
Context Case-control sequencing of RAD51D in 911 breast-ovarian cancer families and 1060 population controls; RNA-interference olaparib-sensitivity assays in CAL51 and MCF7 cells, plus comparison of RAD51D wild-type and RAD51D-deficient CHO cells.
RAD51D | Pathogenic | c.694C[T | p.Arg232* | Nonsense | Not-analyzed
Location Table 2, Description of the deleterious mutations in germinal DNA with the associated tumor Intrinsic Subtype (PAM50)
Context Prospective cohort of 124 unselected patients with triple-negative breast cancer; germline DNA was available and tested for 105 patients using targeted next-generation sequencing with Sanger confirmation of clinically relevant variants.
Of the 360 subjects with primary ovarian, peritoneal, or fallopian tube carcinoma, three (0.83%) carried loss of function mutations in RAD51D (Table 1). Mutations were one nonsense, one frameshift, and one splice-site substitution leading to loss of exon 2 and a frameshift in the RAD51D transcript (Figure 1).
Results, paragraph 1
Screenshots represent source records captured during evidence collection. Select one to view the recorded source content.
The evidence statements recorded by the interpretation pipeline. They have not been reinterpreted by the page.
This variant is present in gnomAD v4.1 (AF= 1.17886e-05; MAF= 0.00118%, 19/1611726 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 3.20513e-05; MAF= 0.00321%, 2/62400 alleles, homozygotes = 0); grpmax FAF= 7.64e-06.
This variant is present in gnomAD v2.1 (AF= 1.44288e-05; MAF= 0.00144%, 4/277224 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 3.16011e-05; MAF= 0.00316%, 4/126578 alleles, homozygotes = 0); grpmax FAF= 7.17e-06.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Pathogenic (28 clinical laboratories) and as pathogenic (1 clinical laboratory) and as Likely pathogenic (1 clinical laboratory). (ClinVarID = 127893)
SpliceAI returned NO scores for this variant, so no SpliceAI-based splice prediction is available. This is missing data, NOT evidence of absent splice impact: it must not be used to support BP4 or to argue against PP3/PVS1. Pangolin scores may be present but are not calibrated for PP3/BP4 here. BayesDel score = 0.63.
OncoKB identified variant-specific curated literature and context relevant to functional review; biological-effect context: Likely Loss-of-function; curated oncogenicity label: Likely Oncogenic.
This variant does not lie in a statistically significant hotspot. This variant has not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.