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.
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.
No pathogenic criterion marked as applied in the recorded assessment.
Met, supporting: RAD51D disease evidence is predominantly loss-of-function while the target is missense.
Met at supporting strength: missense REVEL score 0.287 meets the <=0.29 BP4 supporting threshold.
Met, supporting: c.715C>T repeatedly co-occurred with pathogenic RAD51D c.694C>T, providing an alternate molecular basis for the reported disease.
Likely Benign: BP1, BP4, and BP5, each supporting, satisfy the generic ACMG/AMP fallback rule of at least two supporting benign criteria.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 32 / 1,611,014 alleles. Recorded AF 1.98633e-05. Recorded homozygote count 1.
This variant is present in gnomAD v2.1 (AF= 3.25351e-05; MAF= 0.00325%, 9/276624 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000141323; MAF= 0.01413%, 1/7076 alleles, homozygotes = 0); grpmax FAF= 2.242e-05.
Not available in gnomAD-Canada v1.0.
Recorded REVEL score: 0.287. Refer to the recorded PP3/BP4 rationale for interpretation.
13 Uncertain significance · 2 Likely benign · 1 Uncertain Significance. ClinVar API review status: criteria provided, conflicting classifications.
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.
This variant has previously been reported in somatic cancers (COSMIC; COSV114987211, n = 1 times).
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: 3 met · 11 not met · 9 not assessed · 5 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
The variant is NM_002878.4:c.715C>T, NP_002869.3:p.(Arg239Trp) in RAD51D.
No RAD51D-specific VCEP specification or authoritative domain table was available, so generic ACMG/AMP criteria were used.
The codon/residue evidence supports BP1 at supporting strength; PS1 and PM5 were not established because no qualifying pathogenic same-change or same-residue comparator was documented.
PM1 and PP2 are not met because residue 239 is not established in an approved critical domain or hotspot and RAD51D missense variation is not an established predominant disease mechanism.
No applicable RAD51D-specific VCEP specification was identified, so generic ACMG/AMP criteria were used.
The only variant-specific segregation-related report identified six c.715C>T carriers, but all also carried pathogenic c.694C>T, probably in cis, and the report did not provide parental testing, informative meioses, or a pedigree sufficient to adjudicate PS2, PM6, PP1, or BS4.
No gene-specific VCEP or ClinGen CSPEC framework was available for RAD51D, so generic ACMG/AMP rules were used.
The strongest phenotype/prevalence evidence is recurrent co-occurrence of c.715C>T with pathogenic c.694C>T, supporting BP5; the available case observations do not establish independent PS4 enrichment or a highly specific PP4 phenotype.
ClinVar expert-panel evidence is absent, so neither PP5 nor BP6 is met despite non-expert submissions with Likely benign classifications.
No applicable RAD51D VCEP or gene-specific framework was identified; the supplied generic ACMG/AMP population thresholds were used.
The variant is rare overall in gnomAD v2.1 and v4.1, but ancestry-specific frequencies exceed the generic PM2 threshold while remaining far below BA1 and BS1 thresholds.
One gnomAD v4.1 homozygote is present, but the missing age, health, phenotype, and ascertainment details prevent reliable BS2 application.
No criteria match.
BP1 applies to a missense variant in a gene for which disease is predominantly caused by truncating or other loss-of-function variants. RAD51D loss of function is supported as the germline disease mechanism, and the reviewed RAD51D missense literature does not establish missense variation as a comparable predominant mechanism: among 133 cataloged variants, 59 were missense, but only p.Ser207Leu reached likely pathogenic classification while other missense variants were VUS. The target is a missense variant, so BP1 at supporting strength is met.
Apply BP1 at supporting strength to a missense variant in a gene where pathogenic variation is predominantly truncating or otherwise loss-of-function.
The variant is missense, NP_002869.3:p.(Arg239Trp), so PP3/BP4 must be assessed using REVEL only. REVEL is 0.287, meeting the generic ClinGen SVI calibrated BP4 supporting threshold of <=0.29; therefore BP4 is met at supporting strength. SpliceAI is not substituted for the missense REVEL path, and BayesDel has no generic ACMG strength calibration.
No applicable RAD51D-specific VCEP framework was found, so generic ACMG/AMP BP5 was considered. In PMID:24130102, all six individuals carrying c.715C>T (p.Arg239Trp), including the two ovarian-cancer cases and four healthy carriers, also carried the pathogenic RAD51D c.694C>T (p.Arg232*) variant; the authors state the variants were probably in cis. PMID:22986143 likewise reports p.R239W in an ovarian-carcinoma subject who carried another deleterious RAD51D mutation. This recurrent co-occurrence provides a plausible alternate molecular basis for the disease and supports BP5 at the supporting level, while the uncertain phase and incomplete independent clinical resolution limit confidence.
Generic BP5 supporting: the variant is found in a patient with a definitive molecular diagnosis based on another variant; avoid double counting when the alternate cause is uncertain or phase is unresolved.
No applicable RAD51D-specific VCEP framework was found, so generic ACMG/AMP PS4 was considered. The exact variant is reported in two women with ovarian cancer in a Spanish cohort, but it was also present in four healthy carriers, and the reports do not provide a variant-specific case-control enrichment statistic or a sufficiently controlled comparison. In the ovarian-carcinoma study, p.R239W was observed in one patient, but it co-occurred with another deleterious RAD51D mutation and was not shown to independently enrich in cases versus controls. Therefore the available observations do not establish significant disease enrichment for c.715C>T itself.
Generic PS4: case-control or other statistically supported evidence that the variant is significantly more prevalent in affected individuals than in controls; no fixed numeric threshold was available.
No applicable RAD51D VCEP or gene-specific specification was available, and vcep_materials.json contains no authoritative domain table. The variant is p.Arg239Trp; the available structural paper describes RAD51D nucleotide-binding and BCDX2-complex biology but does not establish residue 239 as a critical functional domain or mutational hotspot. The available hotspot query found no statistically significant hotspot. Accordingly, PM1 is not met.
Apply PM1 only when the variant lies in a well-established critical functional domain or mutational hotspot, using an applicable gene-specific specification when available.
No governing RAD51D VCEP or gene-specific framework was available, so the supplied generic PM2 threshold was applied to the default all-comers gnomAD datasets. Although the overall frequencies are low (gnomAD v4.1 AF 1.98633e-05; gnomAD v2.1 AF 3.25351e-05), the variant exceeds the generic PM2 supporting threshold of 0.0001 in observed ancestry-specific populations: gnomAD v4.1 Middle Eastern AF 0.00084317 and gnomAD v2.1 Remaining individuals AF 0.000141323. The gnomAD v4.1 homozygote further prevents treating the variant as uniformly ultra-rare across populations. Thus PM2 is not met under a conservative ancestry-aware application of the supplied threshold.
{'source': 'generic_svi_recommendation', 'threshold': 'AF <= 0.0001', 'population_measure': 'maximum observed ancestry-specific AF, with overall AF considered for context'}
Generic PP2 requires a gene in which missense variation is an established disease mechanism and benign missense variation is comparatively uncommon. RAD51D disease evidence is centered on loss-of-function and truncating variants, while the reviewed RAD51D missense review cataloged 59 missense variants but identified only p.Ser207Leu as likely pathogenic and several others as VUS. This does not establish missense variation as the predominant RAD51D disease mechanism or the required low benign-missense rate; PP2 is therefore not met.
Apply PP2 only when missense variation is a known disease mechanism for the gene and benign missense variation is uncommon.
The variant is missense, NP_002869.3:p.(Arg239Trp), so PP3/BP4 must be assessed using REVEL only. REVEL is 0.287, below the generic ClinGen SVI calibrated PP3 supporting threshold of >=0.644; therefore PP3 is not met. The unavailable SpliceAI result and uncalibrated BayesDel score are not used for this missense assessment.
No applicable RAD51D-specific VCEP framework was found, so generic ACMG/AMP PP4 was considered. Ovarian cancer and hereditary breast/ovarian cancer-family ascertainment are compatible with RAD51D-associated disease, but they are not sufficiently specific for this variant, and the exact variant was also observed in healthy carriers. The available case reports do not document a highly specific phenotype or a characteristic syndrome presentation that would support PP4.
Generic PP4: phenotype or family history highly specific for a disease with a single-gene etiology; nonspecific ovarian or breast/ovarian cancer history alone is insufficient.
PP5 is restricted here to an exact-variant ClinVar expert-panel classification of Pathogenic or Likely pathogenic. ClinVar identifies the exact NM_002878.4:c.715C>T (p.Arg239Trp) variant, but the submission audit reports zero expert-panel submissions; the available classifications are ordinary laboratory or other non-expert assertions, including Uncertain significance and Likely benign. Therefore PP5 is not met.
PP5 supporting applies only when the exact variant has a ClinVar expert-panel classification of Pathogenic or Likely pathogenic; ordinary submissions and aggregate labels do not qualify.
No governing RAD51D VCEP or gene-specific framework was available, so the generic ACMG/AMP population thresholds were applied to the default all-comers gnomAD datasets. The highest observed ancestry-specific frequency is 0.00084317 in gnomAD v4.1 Middle Eastern individuals, and the total gnomAD v4.1 frequency is 1.98633e-05 (32/1,611,014 alleles); both are below the generic BA1 stand-alone threshold of 0.05. The single observed gnomAD v4.1 homozygote does not alter the allele-frequency comparison.
{'source': 'generic_acmg', 'threshold': 'AF >= 0.05', 'population_measure': 'highest observed ancestry-specific AF and overall AF'}
No governing RAD51D VCEP or gene-specific framework was available, so the supplied generic BS1 threshold was used with the default all-comers gnomAD datasets. The highest observed ancestry-specific frequency is 0.00084317 in gnomAD v4.1 Middle Eastern individuals, while the overall gnomAD v4.1 frequency is 1.98633e-05; both are below the generic BS1 threshold of 0.01. The gnomAD v2.1 maximum observed population frequency, 0.000141323, is also below 0.01.
{'source': 'generic_svi_default', 'threshold': 'AF >= 0.01', 'population_measure': 'highest observed ancestry-specific AF and overall AF'}
No RAD51D-specific VCEP framework was available, so generic ACMG/AMP definitions were considered. BP2 for a dominant disorder requires observation of the variant in trans with a pathogenic variant. The strongest directly relevant report found c.715C>T (p.Arg239Trp) in all six carriers of pathogenic c.694C>T (p.Arg232*) in that series and concluded that the two variants were probably in cis. A separate report lists p.R239W in a patient who also carried deleterious c.694C>T, but does not establish trans phase. Therefore, the available evidence does not satisfy BP2.
Generic ACMG/AMP BP2 for a dominant disorder requires the variant to be observed in trans with a pathogenic variant; no applicable RAD51D VCEP specification was available.
BP6 is restricted here to an exact-variant ClinVar expert-panel classification of Benign or Likely benign. ClinVar identifies the exact variant but reports zero expert-panel submissions. Although two ordinary single-submitter records classify the variant as Likely benign, those non-expert assertions cannot trigger BP6 under the specified rule. Therefore BP6 is not met.
BP6 supporting applies only when the exact variant has a ClinVar expert-panel classification of Benign or Likely benign; ordinary submissions and aggregate labels do not qualify.
PS1 requires a previously established pathogenic variant producing the same amino-acid change, p.Arg239Trp. The reviewed literature confirms this target variant but does not document an independent pathogenic p.Arg239Trp observation, and ClinVar contains conflicting single-submitter classifications without an expert-panel assertion. Therefore, the evidence does not establish PS1; a targeted search for independent pathogenic variants producing p.Arg239Trp remains a gap.
Apply PS1 only when an established pathogenic variant causes the same amino-acid change as the variant under review.
No reliable de novo observation is documented for NM_002878.4:c.715C>T (p.Arg239Trp): the available variant-specific reports describe affected or tested individuals but do not establish that both biological parents were tested and negative. The six carriers reported by PMID:24130102 included two affected women and four healthy carriers, and all also carried the pathogenic c.694C>T variant, reported as probably in cis; this does not establish de novo status for c.715C>T.
Generic ACMG/AMP PS2 requires confirmed de novo occurrence with maternity and paternity confirmed; no applicable RAD51D-specific VCEP specification was identified.
No validated variant-specific functional assay was identified for RAD51D NM_002878.4:c.715C>T (p.Arg239Trp). PMID:22986143 reports p.R239W as a rare missense observation in one ovarian-cancer subject without an experimental functional assessment. PMID:24130102 reports the variant in six individuals, all also carrying the pathogenic c.694C>T allele, and provides only clinical and in-silico observations. PMID:37344587 provides biochemical and structural analyses of the wild-type RAD51D-containing BCDX2 complex but does not test or mention p.Arg239Trp. Therefore, the available evidence does not satisfy PS3 at any strength; a variant-specific assay with appropriate controls and biologically relevant readout would be required.
PM5 requires a different missense change at the same residue that is established as pathogenic. The reviewed evidence documents p.Arg239Trp itself and does not provide a pathogenic alternate missense substitution at Arg239. The nearby RAD51D nonsense variant p.Arg232* is at a different residue and cannot satisfy PM5. Therefore, PM5 cannot be assessed as met from the available comparator evidence.
Apply PM5 only when a different missense change at the same amino-acid residue is established as pathogenic under the applicable framework.
The available reports do not provide a credible assumed-de novo observation for NM_002878.4:c.715C>T (p.Arg239Trp). The variant was reported in six individuals in PMID:24130102, but parental origin was not established, and the observations were confounded because all six also carried pathogenic c.694C>T, probably in cis.
Generic ACMG/AMP PM6 concerns assumed de novo occurrence without confirmation of parental relationships; no applicable RAD51D-specific VCEP specification was identified.
The available evidence does not provide family-based segregation of c.715C>T across informative meioses. PMID:24130102 reports the variant in six individuals, including two affected and four healthy carriers, but all six also carried pathogenic c.694C>T, probably in cis; no pedigree, affected-relative count, phase-resolved transmission series, or meiosis count is provided for c.715C>T itself. Therefore the observations cannot support PP1 or a calibrated strength.
Generic ACMG/AMP PP1 requires co-segregation with disease in multiple affected family members; no applicable RAD51D-specific VCEP threshold or specification was identified.
The default all-comers gnomAD v4.1 data contain one reported homozygote (32 total alleles; 1 homozygote), whereas gnomAD v2.1 contains no homozygotes. This is not sufficient by itself to establish BS2 because the available data do not provide the individual's age, health status, phenotype, ascertainment, or penetrance context, and RAD51D-associated cancer risk is age-dependent and incompletely penetrant. The available evidence therefore cannot confirm or exclude the BS2 requirement of occurrence in an unaffected adult or an informative homozygous observation under the applicable disease model.
{'source': 'generic_acmg', 'threshold': 'Informative observation in an unaffected adult or disease-model-consistent homozygote', 'population_measure': 'homozygote count with phenotype and ascertainment context'}
No validated variant-specific functional assay demonstrating preserved RAD51D function was identified for NM_002878.4:c.715C>T (p.Arg239Trp). PMID:22986143 and PMID:24130102 provide clinical observations and computational predictions, not a controlled benign functional result. PMID:37344587 examines general RAD51D-containing complex biology without testing this variant. Accordingly, the evidence cannot support BS3 at any strength, because neither a normal functional result nor assay validation and controls are available.
Four healthy carriers among the six individuals reported in PMID:24130102 could raise a non-segregation concern, but BS4 cannot be applied from these data alone. The report provides no pedigree, ages and ascertainment details sufficient to exclude age-dependent cancer risk, or phase-resolved analysis separating c.715C>T from the pathogenic c.694C>T variant carried by all six individuals. The healthy-carrier observations therefore do not constitute a documented non-segregation series for c.715C>T.
Generic ACMG/AMP BS4 requires lack of segregation in affected family members or appropriately informative unaffected relatives; no applicable RAD51D-specific VCEP specification was identified.
deterministic_prefilter: requires_null_variant_class
No RAD51D-specific VCEP framework was available, so generic ACMG/AMP definitions were considered. RAD51D hereditary breast/ovarian cancer susceptibility is an autosomal-dominant context, for which PM3 (pathogenic variants in trans in an affected individual with a recessive disorder) is not applicable. The relevant published observation instead reports RAD51D c.715C>T (p.Arg239Trp) together with pathogenic c.694C>T (p.Arg232*) in six individuals, with the authors concluding that the variants were probably in cis; this is not evidence of biallelic disease or a pathogenic variant in trans.
Generic ACMG/AMP PM3 is a recessive-disease criterion requiring a pathogenic variant in trans; no applicable RAD51D VCEP specification was available.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
deterministic_prefilter: requires_repeat_region_indel
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 |
|---|
| Middle Eastern5 / 5,930 | 0.000841 hom |
| African/African American5 / 74,864 | 6.7e-05 |
| Remaining individuals3 / 62,382 | 4.8e-05 |
| East Asian1 / 44,828 | 2.2e-05 |
| Admixed American1 / 59,542 | 1.7e-05 |
| European (non-Finnish)16 / 1,178,930 | 1.4e-05 |
| South Asian1 / 90,320 | 1.1e-05 |
| Remaining individuals1 / 7,076 | 0.00014 |
| East Asian2 / 19,676 | 0.0001 |
| European (non-Finnish)5 / 126,380 | 4e-05 |
| South Asian1 / 29,706 | 3.4e-05 |
This variant is present in gnomAD v4.1 (AF= 1.98633e-05; MAF= 0.00199%, 32/1611014 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.00084317; MAF= 0.08432%, 5/5930 alleles, homozygotes = 1); grpmax FAF= 0.0003318.
This variant is present in gnomAD v2.1 (AF= 3.25351e-05; MAF= 0.00325%, 9/276624 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000141323; MAF= 0.01413%, 1/7076 alleles, homozygotes = 0); grpmax FAF= 2.242e-05.
Not available in gnomAD-Canada v1.0.
The variant is missense, NP_002869.3:p.(Arg239Trp), so PP3/BP4 must be assessed using REVEL only. REVEL is 0.287, meeting the generic ClinGen SVI calibrated BP4 supporting threshold of <=0.29; therefore BP4 is met at supporting strength. SpliceAI is not substituted for the missense REVEL path, and BayesDel has no generic ACMG strength calibration.
The variant is missense, NP_002869.3:p.(Arg239Trp), so PP3/BP4 must be assessed using REVEL only. REVEL is 0.287, below the generic ClinGen SVI calibrated PP3 supporting threshold of >=0.644; therefore PP3 is not met. The unavailable SpliceAI result and uncalibrated BayesDel score are not used for this missense assessment.
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. REVEL score = 0.287. BayesDel score = 0.0376745.
8 paper records listed. 4 cited in the classification.
In addition to the three subjects with RAD51D mutations, five subjects carried rare missense variants in RAD51D: p.C9S, p.S46C, p.S207L, p.R239W, and p.I311N (Table 2).
Location Results, paragraph 5; Table 2, CF 820.01
Context Bidirectional Sanger sequencing of RAD51D exons and intron-exon boundaries in 360 ovarian/peritoneal/fallopian-tube carcinoma subjects and 459 familial breast-cancer patients.
Both the affected and healthy carriers (six subjects) also carried the missense change c.715C>T (p.Arg239Trp) in exon 8 (Table 1).
Location Results, paragraph describing carriers of c.694C>T; Table 1; Discussion
Context Germline RAD51D screening in 842 Spanish index cases from breast and/or ovarian cancer families, using direct sequencing, high-resolution melting, and denaturing high-performance liquid chromatography; protein effects were assessed with four in-silico tools.
For RAD51D only the missense p.(Ser207Leu) founder variant reached a likely pathogenic classification. Four unique variants in RAD51D cause an amino acid change in the residues 132,136 and 138, accounting for a total of 11 reported variants, all of them classified as VUS (Table S4).
Location Results, section 3.3, ‘Missense variants’
Context Literature review integrated with in-house data from four cancer genetics clinics or laboratories; RAD51D germline variants were cataloged and classified.
These glutamates are not conserved in RAD51D or XRCC2 explaining their inability to promote ATP hydrolysis while retaining nucleotide binding.
Location Results, section ‘RAD51B and RAD51C ATPases are coupled,’ paragraph 3
Context Cryo-electron microscopy of the human BCDX2 complex, nucleotide-binding and ATPase assays, ssDNA-binding assays, and single-molecule RAD51 filament-assembly experiments.
The variant classification approach described in this paper is meant to be applicable to variants in all Mendelian genes whether identified by single gene tests, multi-gene panels, exome sequencing or genome sequencing.
Proposed Criteria for Interpretation of Sequence Variants
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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= 1.98633e-05; MAF= 0.00199%, 32/1611014 alleles, homozygotes = 1) and has highest observed frequency in the Middle Eastern population (AF= 0.00084317; MAF= 0.08432%, 5/5930 alleles, homozygotes = 1); grpmax FAF= 0.0003318.
This variant is present in gnomAD v2.1 (AF= 3.25351e-05; MAF= 0.00325%, 9/276624 alleles, homozygotes = 0) and has highest observed frequency in the Remaining individuals population (AF= 0.000141323; MAF= 0.01413%, 1/7076 alleles, homozygotes = 0); grpmax FAF= 2.242e-05.
Not available in gnomAD-Canada v1.0.
This variant has been reported in ClinVar as Uncertain significance (13 clinical laboratories) and as Likely benign (2 clinical laboratories) and as Uncertain Significance (1 clinical laboratory). (ClinVarID = 187225)
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. REVEL score = 0.287. BayesDel score = 0.0376745.
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.
This variant does not lie in a statistically significant hotspot. This variant has previously been reported in somatic cancers (COSMIC; COSV114987211, n = 1 times).
This variant does not lie in a statistically significant hotspot.