The RAD51D NM_002878.4:c.355T>C (NP_002869.3:p.(Cys119Arg)) missense variant has not previously been reported in somatic cancers (COSMIC). Based on available guidelines, this variant is considered to be a Variant of Uncertain Significance (VUS).
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.
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 Generic ACMG/AMP 2015 with ClinGen SVI recommendations. 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 at supporting: missense REVEL 0.219 meets the generic BP4 supporting threshold of <=0.29.
VUS: BP4 (supporting) is the only applied criterion, and one supporting benign criterion does not satisfy a generic ACMG benign or likely benign combination rule.
Evidence summaries and captured source records, where available. Missing entries should not be interpreted as negative findings.
gnomAD v4.1: 219 / 1,613,972 alleles. Recorded AF 0.00013569. Recorded homozygote count 1.
This variant is present in gnomAD v2.1 (AF= 5.30425e-05; MAF= 0.00530%, 15/282792 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.51604e-05; MAF= 0.00852%, 11/129168 alleles, homozygotes = 0); grpmax FAF= 4.114e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 5.431830526887561e-05, 1/18410 alleles, homozygotes = 0).
Recorded REVEL score: 0.219. Refer to the recorded PP3/BP4 rationale for interpretation.
11 Uncertain significance · 3 Likely benign. 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 not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.
ACMG/AMP criteria under Generic ACMG/AMP 2015 with ClinGen SVI recommendations, with the data and sources behind each one.
28 criteria with recorded statuses: 1 met · 6 not met · 17 not assessed · 4 not applicable. Open any row for the full reasoning, the rule and the evidence behind it.
No VCEP covers RAD51D in this case; generic ACMG/AMP rules govern.
The exact variant is documented in cancer cohorts, but no variant-specific case-control estimate satisfies PS4 and no sufficiently specific phenotype is documented for PP4.
ClinVar provides no expert-panel exact-variant Pathogenic, Likely pathogenic, Benign, or Likely benign assertion; therefore PP5 and BP6 are not triggered.
Generic ACMG/AMP rules govern because no VCEP covers RAD51D.
The missense consequence selects the REVEL-only computational path; SpliceAI is not double-counted or substituted.
No criteria match.
The variant is a missense substitution, so the generic PP3/BP4 missense path requires REVEL and excludes SpliceAI for this criterion. REVEL is 0.219, which is <= 0.29 and meets the generic BP4 supporting cutoff; therefore BP4 is met at supporting strength. BayesDel is not available for generic ACMG/AMP strength assignment.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
PM2 is not met under the default all-comers population source because the variant is present in gnomAD v4.1 at AF 0.00013569 (219/1,613,972 alleles), above the generic PM2 supporting threshold of <= 0.0001. Its gnomAD v4.1 grpmax FAF is 0.0001554. Earlier gnomAD v2.1 all-comers and the available non-cancer subsets are below 0.0001, but no VCEP or governing rule requires those subsets for this generic RAD51D interpretation; the prompt specifies all-comers GNOMAD_V2_1/GNOMAD_V4_1 as the default. Therefore the current all-comers v4 observation prevents PM2, despite the low absolute frequency and absence of homozygotes in v2/non-cancer datasets.
PM2 (supporting): <= 0.0001 — SVI recommendation to downgrade PM2 to Supporting (ClinGen SVI 2020) (PMID:25741868)
The variant is a missense substitution, so the generic PP3/BP4 missense path requires REVEL and excludes SpliceAI for this criterion. REVEL is 0.219, below the generic PP3 supporting cutoff of >= 0.644; therefore PP3 is not met. BayesDel is not available for generic ACMG/AMP strength assignment.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
Generic PP5 requires a reputable source to recently report the variant as pathogenic when the underlying evidence is unavailable for independent evaluation. ClinVar variation 182856 has no expert-panel submissions and reports conflicting classifications: 11 laboratories as uncertain significance and 3 as likely benign. No exact-variant ClinVar expert-panel Pathogenic or Likely pathogenic classification is present. Ordinary laboratory submissions, aggregate labels, and non-expert assertions do not satisfy the specified PP5 rule.
Reputable source recently reports variant as pathogenic, but the evidence is not available to the laboratory to perform an independent evaluation.
BA1 is not met. In the default all-comers datasets, the gnomAD v4.1 grpmax FAF is 0.0001554 (0.01554%), far below the generic stand-alone threshold of >= 0.05 (5%). The corresponding gnomAD v4.1 total AF is 0.00013569 from 219/1,613,972 alleles, and the highest-frequency population has 1,180,004 observed alleles, satisfying the minimum population-size safeguard. gnomAD v2.1 also has grpmax FAF 0.00004114. No frequency evidence approaches BA1, so the conflicting ClinVar classifications do not create a BA1 call.
BA1 (stand-alone): >= 0.05 — ACMG/AMP 2015 stand-alone benign allele frequency (PMID:25741868)
BS1 is not met. The governing generic default is allele frequency >= 0.01, but the appropriate filtering value in the default all-comers gnomAD data is the v4.1 grpmax FAF of 0.0001554 (0.01554%), which is below 1%. The frequency is therefore not greater than expected for the disorder on the supplied generic threshold; no maximum-credible-frequency calculation is needed to rescue or reject a frequency that is already more than 60-fold below the default. The gnomAD v4.1 highest-frequency population contains 1,180,004 observed alleles, so this conclusion does not rely on a small isolate population or a popmax point estimate.
BS1 (strong): >= 0.01 — Generic SVI default; per-gene derivation preferred (Whiffin et al. 2017) (PMID:28518168)
Generic BP6 requires a reputable source to recently report the variant as benign when the underlying evidence is unavailable for independent evaluation. ClinVar variation 182856 has no expert-panel submissions; its Likely benign classifications are ordinary laboratory submissions, while the aggregate record is conflicting and includes uncertain-significance submissions. Under the specified generic rule, these non-expert assertions cannot trigger BP6.
Reputable source recently reports variant as benign, but the evidence is not available to the laboratory to perform an independent evaluation.
The variant is RAD51D NM_002878.4:c.355T>C (p.Cys119Arg). PMID:22415235 reports this exact missense variant and describes it as most likely benign, not as an established pathogenic variant. The available evidence does not establish a pathogenic RAD51D variant producing the same amino-acid change by another nucleotide change, and a comprehensive pathogenic-variant comparison was not available.
Same amino acid change as a previously established pathogenic variant regardless of nucleotide change.
PS2 cannot be assessed. The available variant report states that c.355T>C (p.Cys119Arg) was observed in a Belgian family, but it does not report a de novo finding, confirmed maternity, confirmed paternity, or absence of family history for the proband.
De novo (both maternity and paternity confirmed) in a patient with the disease and no family history.
No validated in vitro or in vivo functional assay for RAD51D c.355T>C (p.Cys119Arg) was identified. Osher et al. reported the variant with SIFT and PolyPhen2 predictions only, and Gutiérrez-Enríquez et al. reported in silico predictions and no functional assay; therefore the available evidence does not establish a damaging functional effect or support PS3 at any strength. The ClinVar-linked PMID:25085752 is not available in the extracted full-text evidence and its citation alone cannot establish functional findings.
Well-established in vitro or in vivo functional studies supportive of a damaging effect on the gene or gene product.
Generic ACMG/AMP PS4 requires a significantly increased prevalence in affected individuals compared with controls, with RR or OR >5.0 and a confidence interval that does not include 1.0. PMID:22415235 reports the exact variant in one Belgian cancer family but does not provide a matched control comparison or variant-specific frequency; PMID:24130102 reports the exact variant in 1 of 842 Spanish index cases but does not provide a matched control comparison or variant-specific confidence interval. PMID:26261251 is a case-control study of RAD51D variants, but its extract explicitly states that c.355T>C/p.Cys119Arg was not reported, so its gene-level missense burden result cannot be transferred to this variant. Therefore a variant-specific OR/RR and 95% CI are unavailable, and PS4 cannot be adjudicated.
The prevalence of the variant in affected individuals is significantly increased compared to the prevalence in controls. Note 1: Relative risk (RR) or odds ratio (OR), as obtained from case-control studies, is >5.0 and the confidence interval around the estimate of RR or OR does not include 1.0.
RAD51D p.Cys119Arg is a missense variant. The case has no VCEP domain table for RAD51D, and no authoritative critical-domain annotation for residue 119 is supplied. Cancer Hotspots reports no statistically significant hotspot for RAD51D C119, and COSMIC reports no somatic occurrence for this variant, but those negative observations do not establish whether residue 119 lies in a critical functional domain without benign variation.
Located in a mutational hot spot and/or critical and well-established functional domain (e.g. active site of an enzyme) without benign variation.
PM3 cannot be assessed from the available evidence. The governing rule requires a recessive disorder and detection of the variant in trans with a pathogenic variant, with parental or offspring testing to establish phase. RAD51D c.355T>C (p.Cys119Arg) was reported in a Belgian family, but the report provides no pathogenic allele in the same individual, no cis/trans relationship, no parental or offspring testing, and no sufficient inheritance-mode specification for this case.
PM3: For recessive disorders, detected in trans with a pathogenic variant ... Note: This requires testing of parents (or offspring) to determine phase.
The variant affects RAD51D residue Cys119. No different missense substitution at residue 119 with an established pathogenic determination is identified in the available evidence. The exact variant was reported as most likely benign by PMID:22415235, while the available PM5 candidate collection contains zero same-residue candidates; this is insufficient for a definitive comprehensive negative conclusion.
Novel missense change at an amino acid residue where a different missense change determined to be pathogenic has been seen before.
PM6 cannot be assessed. The available variant report only states that c.355T>C (p.Cys119Arg) was observed in a Belgian family; it provides no evidence that the variant was assumed to be de novo and no parental testing result.
Assumed de novo, but without confirmation of paternity and maternity.
PP1 cannot be assessed. The available report identifies c.355T>C (p.Cys119Arg) in a Belgian family but provides no affected-relative genotypes, cosegregation results, number of informative meioses, or other segregation evidence for this variant.
Co-segregation with disease in multiple affected family members in a gene definitively known to cause the disease. ... Note: May be used as stronger evidence with increasing segregation data.
The available evidence does not establish both required components of PP2: that RAD51D has a low rate of benign missense variation and that missense variants are a common disease mechanism. The case provides population frequency for this variant and evidence that RAD51D truncating variants are disease-relevant, but not a gene-wide benign-missense rate or a demonstrated common missense mechanism.
Missense variant in a gene that has a low rate of benign missense variation and where missense variants are a common mechanism of disease.
The generic PP4 rule requires a patient's phenotype or family history to be highly specific for a disease with a single genetic etiology. The available evidence identifies the variant in cancer-family or cancer-screening cohorts but does not provide a sufficiently specific phenotype or family-history description for this patient, nor establish a single-gene etiology for the reported presentation. PP4 therefore cannot be assessed.
Patient’s phenotype or family history is highly specific for a disease with a single genetic etiology.
BS2 is not assessed. gnomAD v4.1 reports one homozygote among 1,613,972 alleles, whereas gnomAD v2.1 and the non-cancer subsets report no homozygotes. That single database homozygote does not establish observation in a healthy adult individual, because no age, phenotype, medical-history, or cancer-status information for the individual is provided. RAD51D-associated hereditary breast/ovarian cancer susceptibility is an adult-onset cancer-predisposition context, and the required assumption of full penetrance at an early age is not established here. A human reviewer would need verified healthy-adult phenotype and age information, plus an appropriate penetrance assessment, before applying BS2.
Observed in a healthy adult individual for a recessive (homozygous), dominant (heterozygous), or X-linked (hemizygous) disorder, with full penetrance expected at an early age.
No validated in vitro or in vivo functional assay for RAD51D c.355T>C (p.Cys119Arg) was identified. Osher et al. and Gutiérrez-Enríquez et al. reported computationally benign or tolerated predictions but did not demonstrate experimentally that the variant has no damaging effect on protein function or splicing. Thus the available evidence is insufficient to apply BS3 at any strength.
Well-established in vitro or in vivo functional studies show no damaging effect on protein function or splicing.
BS4 cannot be assessed. The available report does not identify affected relatives who lack the variant, does not provide relative genotypes or phenotypes, and therefore supplies no evidence of non-segregation. The phenocopy caveat also cannot be evaluated without family-level clinical information.
Lack of segregation in affected members of a family. ... Caveat: The presence of phenocopies for common phenotypes (i.e. cancer, epilepsy) can mimic lack of segregation among affected individuals.
RAD51D is associated with disease-relevant germline truncating variants, but the available evidence does not establish that primarily truncating variants are known to cause disease or that missense variants are generally not a disease mechanism. Therefore the BP1 gene-level prerequisite cannot be confirmed from the supplied evidence.
Missense variant in a gene for which primarily truncating variants are known to cause disease.
BP2 cannot be assessed from the available evidence. The governing rule requires observation in trans with a pathogenic variant for a fully penetrant dominant gene/disorder, or observation in cis with a pathogenic variant in any inheritance pattern. The available report only identifies RAD51D c.355T>C (p.Cys119Arg) in a Belgian family and provides no second pathogenic variant, phase, or affected-proband genotype; therefore neither the trans nor cis BP2 pathway is demonstrated.
Observed in trans with a pathogenic variant for a fully penetrant dominant gene/disorder or observed in cis with a pathogenic variant in any inheritance pattern.
The generic BP5 rule requires the variant to be found in a case with an alternate molecular basis for disease. The reviewed exact-variant reports describe cancer cohorts or families but do not document an alternate molecular diagnosis in a case carrying RAD51D c.355T>C, and no such case evidence is present in the available records. BP5 cannot therefore be assessed.
Variant found in a case with an alternate molecular basis for disease.
PVS1 (ClinGen SVI PVS1 recommendations, PMC6185798, pvs1_generic_framework) applies only to null variant classes — nonsense, frameshift, canonical ±1/2 splice-consensus, translation-initiation-codon loss, and stop-loss variants — each expected to trigger nonsense-mediated decay or otherwise abolish normal protein function. NM_002878.4:c.355T>C in RAD51D is a missense substitution predicted to produce NP_002869.3:p.(Cys119Arg). As a result, no null-variant mechanism (nonsense-mediated decay, truncation, or canonical splice disruption) is triggered by this variant class, so PVS1's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PVS1 for RAD51D, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_null_variant_class
PM4 (Richards et al. 2015, PMID:25741868) applies to protein length changes: in-frame insertions/deletions in a non-repetitive region, or stop-loss variants that extend the protein past the reference stop codon. NM_002878.4:c.355T>C in RAD51D is a missense substitution predicted to produce NP_002869.3:p.(Cys119Arg). As a result, no change in protein length occurs, so there is nothing for this criterion to evaluate, so PM4's structural prerequisite is not met by this variant class. No VCEP criteria specification covers PM4 for RAD51D, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_stop_loss_or_nonrepeat_indel
BP3 (Richards et al. 2015, PMID:25741868) applies to in-frame insertions/deletions located in a repetitive region without a known function. NM_002878.4:c.355T>C in RAD51D is a missense substitution predicted to produce NP_002869.3:p.(Cys119Arg). As a result, the variant does not alter protein length within a repeat region, so there is nothing for this criterion to evaluate, so BP3's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP3 for RAD51D, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_repeat_region_indel
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002878.4:c.355T>C in RAD51D is a missense substitution predicted to produce NP_002869.3:p.(Cys119Arg). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for RAD51D, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
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 |
|---|
| European (non-Finnish)207 / 1,180,004 | 0.000181 hom |
| Admixed American7 / 60,010 | 0.00012 |
| Remaining individuals3 / 62,484 | 4.8e-05 |
| African/African American2 / 74,916 | 2.7e-05 |
| European (non-Finnish)11 / 129,168 | 8.5e-05 |
| Admixed American3 / 35,440 | 8.5e-05 |
| African/African American1 / 24,960 | 4e-05 |
This variant is present in gnomAD v4.1 (AF= 0.00013569; MAF= 0.01357%, 219/1613972 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000175423; MAF= 0.01754%, 207/1180004 alleles, homozygotes = 1); grpmax FAF= 0.0001554.
This variant is present in gnomAD v2.1 (AF= 5.30425e-05; MAF= 0.00530%, 15/282792 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.51604e-05; MAF= 0.00852%, 11/129168 alleles, homozygotes = 0); grpmax FAF= 4.114e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 5.431830526887561e-05, 1/18410 alleles, homozygotes = 0).
The variant is a missense substitution, so the generic PP3/BP4 missense path requires REVEL and excludes SpliceAI for this criterion. REVEL is 0.219, which is <= 0.29 and meets the generic BP4 supporting cutoff; therefore BP4 is met at supporting strength. BayesDel is not available for generic ACMG/AMP strength assignment.
Multiple lines of computational evidence suggest no impact on gene or gene product (conservation, evolutionary, splicing impact, etc)
The variant is a missense substitution, so the generic PP3/BP4 missense path requires REVEL and excludes SpliceAI for this criterion. REVEL is 0.219, below the generic PP3 supporting cutoff of >= 0.644; therefore PP3 is not met. BayesDel is not available for generic ACMG/AMP strength assignment.
Multiple lines of computational evidence support a deleterious effect on the gene or gene product (conservation, evolutionary, splicing impact, etc.).
BP7 (Richards et al. 2015, PMID:25741868) is defined for a synonymous (silent) variant for which splicing prediction algorithms predict no impact to the splice consensus sequence and the nucleotide is not highly conserved. NM_002878.4:c.355T>C in RAD51D is a missense substitution predicted to produce NP_002869.3:p.(Cys119Arg). As a result, the encoded protein sequence is altered, so the criterion's silent-variant premise does not hold regardless of any splicing prediction, so BP7's structural prerequisite is not met by this variant class. No VCEP criteria specification covers BP7 for RAD51D, so the generic ACMG/AMP 2015 definition applies. This determination was made deterministically from the variant's consequence class, prior to LLM adjudication.
deterministic_prefilter: requires_synonymous
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). REVEL score = 0.219. BayesDel score = -0.0660511.
8 paper records listed. No publication is explicitly linked to an applied criterion in the recorded metadata.
The first, p.Cys119Arg (c.355T>C), is a novel missense variant observed in a Belgian family, and is predicted to be tolerated by SIFT analysis and benign by Polyphen2 analysis. ... Both these variants are most likely benign.
Results, paragraph beginning “Three additional variants were identified” (Supplementary Table 1B)
We also found some evidence of an association of missense variants in RAD51D with an increased risk of serous ovarian cancer (P = .012).
Results, ‘RAD51B, RAD51C, and RAD51D Missense Variants and Ovarian Cancer Risk’; Table 2
In addition, RAD51C and RAD51D germline truncations are positively correlated with increased somatic mutation frequencies in ovarian cancer.
Results, Somatic and germline interactions and clinical associations, paragraph discussing Fig. 5b
Five missense variants, c.26G>C (p.Cys9Ser; rs140825795), c.355T>C (p.Cys119Arg; rs201313861), c.629C>T (p.Ala210Val), c.695G>A (p.Arg232Gln; rs28363283) and c.715C>T (p.Arg239Trp), have been reported with a minor allele frequency (MAF) of 0.0001 to 0.003 in either 1000 genomes and ESP databases as well as in previous studies11,14,22 (Table 1).
Results, paragraph beginning ‘We also identified seven RAD51D nonsynonymous variants’; Table 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= 0.00013569; MAF= 0.01357%, 219/1613972 alleles, homozygotes = 1) and has highest observed frequency in the European (non-Finnish) population (AF= 0.000175423; MAF= 0.01754%, 207/1180004 alleles, homozygotes = 1); grpmax FAF= 0.0001554.
This variant is present in gnomAD v2.1 (AF= 5.30425e-05; MAF= 0.00530%, 15/282792 alleles, homozygotes = 0) and has highest observed frequency in the European (non-Finnish) population (AF= 8.51604e-05; MAF= 0.00852%, 11/129168 alleles, homozygotes = 0); grpmax FAF= 4.114e-05.
This variant is present in gnomAD-Canada v1.0 (AF= 5.431830526887561e-05, 1/18410 alleles, homozygotes = 0).
This variant has been reported in ClinVar as Uncertain significance (11 clinical laboratories) and as Likely benign (3 clinical laboratories). (ClinVarID = 182856)
SpliceAI predicts no significant splice impact for this variant (max delta score = 0.15). REVEL score = 0.219. BayesDel score = -0.0660511.
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 not previously been reported in somatic cancers (COSMIC).
This variant does not lie in a statistically significant hotspot.