rs1409088398
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Variant summary
Our verdict is Pathogenic. Variant got 18 ACMG points: 18P and 0B. PVS1PM2PP5_Very_Strong
The NM_002878.4(RAD51D):c.641dupC(p.Leu215fs) variant causes a frameshift change involving the alteration of a non-conserved nucleotide. The variant allele was found at a frequency of 0.000000684 in 1,461,884 control chromosomes in the GnomAD database, with no homozygous occurrence. Variant has been reported in ClinVar as Likely pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Genomes: not found (cov: 32)
Exomes 𝑓: 6.8e-7 ( 0 hom. )
Consequence
RAD51D
NM_002878.4 frameshift
NM_002878.4 frameshift
Scores
Not classified
Clinical Significance
Conservation
PhyloP100: 2.64
Genes affected
RAD51D (HGNC:9823): (RAD51 paralog D) The protein encoded by this gene is a member of the RAD51 protein family. RAD51 family members are highly similar to bacterial RecA and Saccharomyces cerevisiae Rad51, which are known to be involved in the homologous recombination and repair of DNA. This protein forms a complex with several other members of the RAD51 family, including RAD51L1, RAD51L2, and XRCC2. The protein complex formed with this protein has been shown to catalyze homologous pairing between single- and double-stranded DNA, and is thought to play a role in the early stage of recombinational repair of DNA. Alternative splicing results in multiple transcript variants. Read-through transcription also exists between this gene and the downstream ring finger and FYVE-like domain containing 1 (RFFL) gene. [provided by RefSeq, Jan 2011]
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ACMG classification
Classification made for transcript
Verdict is Pathogenic. Variant got 18 ACMG points.
PVS1
Loss of function variant, product undergoes nonsense mediated mRNA decay. LoF is a known mechanism of disease.
PM2
Very rare variant in population databases, with high coverage;
PP5
Variant 17-35103479-T-TG is Pathogenic according to our data. Variant chr17-35103479-T-TG is described in ClinVar as [Likely_pathogenic]. Clinvar id is 492434.Status of the report is criteria_provided_multiple_submitters_no_conflicts, 2 stars.
Transcripts
RefSeq
Ensembl
Frequencies
GnomAD3 genomes
GnomAD3 genomes
Cov.:
32
GnomAD4 exome AF: 6.84e-7 AC: 1AN: 1461884Hom.: 0 Cov.: 32 AF XY: 0.00000138 AC XY: 1AN XY: 727244
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GnomAD4 genome
GnomAD4 genome
Cov.:
32
ClinVar
Significance: Likely pathogenic
Submissions summary: Pathogenic:5
Revision: criteria provided, multiple submitters, no conflicts
LINK: link
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:3
| Likely pathogenic, criteria provided, single submitter | clinical testing | Labcorp Genetics (formerly Invitae), Labcorp | Apr 15, 2024 | This sequence change creates a premature translational stop signal (p.Leu215Thrfs*112) in the RAD51D gene. While this is not anticipated to result in nonsense mediated decay, it is expected to disrupt the last 114 amino acid(s) of the RAD51D protein. This variant is present in population databases (no rsID available, gnomAD 0.003%). This variant has not been reported in the literature in individuals affected with RAD51D-related conditions. ClinVar contains an entry for this variant (Variation ID: 492434). This variant disrupts the ATPase domain and RAD51C interaction domain of the RAD51D protein, which are necessary for the DNA repair activity (PMID: 14704354, 19327148, 21111057, 10749867). While functional studies have not been performed to directly test the effect of this variant on RAD51D protein function, this suggests that disruption of this region of the protein is causative of disease. In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Nov 30, 2023 | This variant is considered likely pathogenic. This variant creates a frameshift predicted to result in premature protein truncation. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Jun 20, 2022 | - - |
Hereditary cancer-predisposing syndrome Pathogenic:2
| Likely pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Jun 21, 2022 | The c.641dupC variant, located in coding exon 7 of the RAD51D gene, results from a duplication of C at nucleotide position 641, causing a translational frameshift with a predicted alternate stop codon (p.L215Tfs*112). This alteration occurs at the 3' terminus of theRAD51D gene, is not expected to trigger nonsense-mediated mRNA decay, and impacts the last 114 amino acids of the protein. However, premature stop codons are typically deleterious in nature and the impacted region is critical for protein function (Ambry internal data). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). Based on the majority of available evidence to date, this variant is likely to be pathogenic. - |
| Likely pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 03, 2019 | - - |
Computational scores
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SpliceAI score (max)
Details are displayed if max score is > 0.2
Find out detailed SpliceAI scores and Pangolin per-transcript scores at