rs1057521922
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_002878.4(RAD51D):c.478C>T(p.Gln160Ter) variant causes a stop gained, splice region change involving the alteration of a conserved nucleotide. The variant allele was found at a frequency of 0.0000103 in 1,461,894 control chromosomes in the GnomAD database, with no homozygous occurrence. In-silico tool predicts a pathogenic outcome for this variant. Variant has been reported in ClinVar as Pathogenic (★★). Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_002878.4 stop_gained, splice_region
Scores
Clinical Significance
Conservation
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ACMG classification
Verdict is Pathogenic. Variant got 16 ACMG points.
Transcripts
RefSeq
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | MANE | UniProt |
---|---|---|---|---|---|---|---|
RAD51D | NM_002878.4 | c.478C>T | p.Gln160Ter | stop_gained, splice_region_variant | 5/10 | ENST00000345365.11 | |
RAD51L3-RFFL | NR_037714.1 | n.233-509C>T | intron_variant, non_coding_transcript_variant |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51D | ENST00000345365.11 | c.478C>T | p.Gln160Ter | stop_gained, splice_region_variant | 5/10 | 1 | NM_002878.4 | P1 |
Frequencies
GnomAD3 genomes ? Cov.: 31
GnomAD4 exome AF: 0.0000103 AC: 15AN: 1461894Hom.: 0 Cov.: 32 AF XY: 0.00000825 AC XY: 6AN XY: 727248
GnomAD4 genome ? Cov.: 31
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jan 22, 2018 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Myriad Genetics, Inc. | Apr 06, 2023 | This variant is considered pathogenic. This variant creates a termination codon and is predicted to result in premature protein truncation. - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Dec 22, 2023 | This sequence change creates a premature translational stop signal (p.Gln160*) in the RAD51D gene. It is expected to result in an absent or disrupted protein product. Loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). This variant is not present in population databases (gnomAD no frequency). This premature translational stop signal has been observed in individual(s) with breast or ovarian cancer (PMID: 25452441, 26261251). ClinVar contains an entry for this variant (Variation ID: 384322). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Dec 25, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Oct 07, 2021 | - - |
not provided Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Apr 16, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | May 24, 2018 | This variant is denoted RAD51D c.478C>T at the cDNA level and p.Gln160Ter (Q160X) at the protein level. The substitution creates a nonsense variant, which changes a Glutamine to a premature stop codon (CAG>TAG), and is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. This variant has been reported in at least one woman with epithelial ovarian cancer and another with triple negative breast cancer (Couch 2015, Song 2015). Based on current evidence, we consider this variant to be pathogenic. - |
Hereditary cancer-predisposing syndrome Pathogenic:2
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Dec 06, 2023 | This variant changes 1 nucleotide in exon 5 of the RAD51D gene, creating a premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in one individual each affected with ovarian cancer (PMID: 26261251) and breast cancer (PMID: 25452441). This variant also has been reported in a breast cancer case-control meta-analysis in 4/60466 cases and 0/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51D_000014). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of RAD51D function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Ambry Genetics | Apr 07, 2022 | The p.Q160* pathogenic mutation (also known as c.478C>T), located in coding exon 5 of the RAD51D gene, results from a C to T substitution at nucleotide position 478. This changes the amino acid from a glutamine to a stop codon within coding exon 5. This mutation has been identified in a patient with ovarian cancer and in a patient with triple-negative breast cancer (Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Couch FJ et al. J. Clin. Oncol. 2015 Feb;33:304-11). In addition to the clinical data presented in the literature, this alteration is expected to result in loss of function by premature protein truncation or nonsense-mediated mRNA decay. As such, this alteration is interpreted as a disease-causing mutation. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at