rs387906843
Variant summary
Our verdict is Pathogenic. Variant got 16 ACMG points: 16P and 0B. PVS1PP5_Very_Strong
The NM_002878.4(RAD51D):c.556C>T(p.Arg186Ter) variant causes a stop gained change. The variant allele was found at a frequency of 0.000031 in 1,612,962 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 (★★). Synonymous variant affecting the same amino acid position (i.e. R186R) has been classified as Likely benign. Variant results in nonsense mediated mRNA decay.
Frequency
Consequence
NM_002878.4 stop_gained
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.556C>T | p.Arg186Ter | stop_gained | 6/10 | ENST00000345365.11 | |
RAD51L3-RFFL | NR_037714.1 | n.308C>T | non_coding_transcript_exon_variant | 2/7 |
Ensembl
Gene | Transcript | HGVSc | HGVSp | Effect | #exon/exons | TSL | MANE | Appris | UniProt |
---|---|---|---|---|---|---|---|---|---|
RAD51D | ENST00000345365.11 | c.556C>T | p.Arg186Ter | stop_gained | 6/10 | 1 | NM_002878.4 | P1 |
Frequencies
GnomAD3 genomes ? AF: 0.0000263 AC: 4AN: 152156Hom.: 0 Cov.: 32
GnomAD3 exomes AF: 0.0000401 AC: 10AN: 249290Hom.: 0 AF XY: 0.0000445 AC XY: 6AN XY: 134760
GnomAD4 exome AF: 0.0000315 AC: 46AN: 1460806Hom.: 0 Cov.: 31 AF XY: 0.0000275 AC XY: 20AN XY: 726582
GnomAD4 genome ? AF: 0.0000263 AC: 4AN: 152156Hom.: 0 Cov.: 32 AF XY: 0.00 AC XY: 0AN XY: 74314
ClinVar
Submissions by phenotype
Breast-ovarian cancer, familial, susceptibility to, 4 Pathogenic:8Other:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RAD51D p.Arg186X variant was identified in 7 of 15516 proband chromosomes (frequency: 0.00045) from individuals or families with breast and/or ovarian cancer or at high risk of ovarian cancer and was not identified in 7744 control chromosomes from healthy individuals (Loveday 2011, Song 20015, Thompson 2013, Keen-Kim 2017, Osher 2012). The variant was also identified in dbSNP (ID: rs387906843) as “With Pathogenic allele”, ClinVar (classified 5x as pathogenic by Ambry Genetics, Invitae, Counsyl, Color Genomics and GeneDx; classified as risk factor by OMIM), Clinvitae (same references as ClinVar), databases. The variant was not identified in the COSMIC database. The variant was identified in control databases in 8 of 275060 chromosomes at a frequency of 0.00003 in the following populations: Ashkenazi Jewish in 4 of 10036 chromosomes (freq. 0.0004); European non-Finnish in 4 of 125824 chromosomes (freq. 0.00003), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). This variant was identified in 2 Canadian individuals with ovarian cancer from the same family, both of whom demonstrated loss of wild-type allele in DNA extracted from tumour cells (Osher 2012). In a 3-generation pedigree segregating ovarian cancer and breast cancer this variant was found in 4 members of the same family (Loveday 2011). The proband had ovarian cancer at age 38; the variant was also confirmed in her sister who had breast cancer at age 39, and two aunts who had breast cancer at age 58 and age 53. Four other relatives on whom no molecular testing could be done died of ovarian cancer ranging in age from 49 to 65 years. Loss of function variants of the RAD51D gene are an established mechanism of disease in breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
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. - |
risk factor, no assertion criteria provided | literature only | OMIM | Aug 07, 2011 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Mendelics | May 28, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Counsyl | Jun 09, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | MGZ Medical Genetics Center | Mar 08, 2022 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Baylor Genetics | Mar 14, 2024 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Invitae | Jan 16, 2024 | This sequence change creates a premature translational stop signal (p.Arg186*) 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 present in population databases (rs387906843, gnomAD 0.04%). This premature translational stop signal has been observed in individual(s) with ovarian and breast cancer (PMID: 21822267, 22415235, 23372765, 25445424, 26261251). It has also been observed to segregate with disease in related individuals. ClinVar contains an entry for this variant (Variation ID: 30285). For these reasons, this variant has been classified as Pathogenic. - |
Pathogenic, criteria provided, single submitter | clinical testing | Fulgent Genetics, Fulgent Genetics | Aug 04, 2021 | - - |
not provided Pathogenic:5
Pathogenic, criteria provided, single submitter | clinical testing | PreventionGenetics, part of Exact Sciences | Nov 02, 2016 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Revvity Omics, Revvity | Jul 30, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | CeGaT Center for Human Genetics Tuebingen | Dec 01, 2019 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | Quest Diagnostics Nichols Institute San Juan Capistrano | Oct 26, 2017 | - - |
Pathogenic, criteria provided, single submitter | clinical testing | GeneDx | Sep 13, 2023 | Nonsense variant predicted to result in protein truncation or nonsense mediated decay in a gene for which loss of function is a known mechanism of disease; Not observed at significant frequency in large population cohorts (gnomAD); This variant is associated with the following publications: (PMID: 27273131, 32242007, 30165555, 32986223, 28888541, 21822267, 25445424, 19383352, 22415235, 26328243, 26261251, 27153395, 23372765, 29560538, 28724667, 28821472, 26057125, 28152038, 30111881, 28591191, 30980208, 26689913, 32068069, 32885271, 32338768, 32107557, 35641994, 33804961, 32191290, 36346689, 36544182, 36169650, 32359370, 33471991, 32295079) - |
Hereditary cancer-predisposing syndrome Pathogenic:3
Pathogenic, criteria provided, single submitter | clinical testing | Color Diagnostics, LLC DBA Color Health | Apr 17, 2023 | This variant changes 1 nucleotide in exon 6 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 observed in multiple individuals affected with ovarian cancer (PMID: 21822267, 22415235, 23372765, 26261251, 32068069, 36544182), breast cancer (PMID: 21822267, 22415235, 27153395, 27273131), and in an individual affected with endometrial and serous tubal intraepithelial cancer (PMID: 28821472). This variant has also been detected in a breast cancer case-control meta-analysis in 6/60466 cases and 1/53461 unaffected individuals (PMID: 33471991; Leiden Open Variation Database DB-ID RAD51D_000017). This variant has been identified in 12/280688 chromosomes 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 | Nov 16, 2021 | The p.R186* pathogenic mutation (also known as c.556C>T), located in coding exon 6 of the RAD51D gene, results from a C to T substitution at nucleotide position 556. This changes the amino acid from an arginine to a stop codon within coding exon 6. This mutation has been described in several breast and/or ovarian cancer patients (Loveday C et al. Nat. Genet. 2011 Sep;43:879-82; Osher D et al. Br. J. Cancer. 2012 Apr;106:1460-3; Song H et al. J. Clin. Oncol. 2015 Sep;33:2901-7; Maxwell KN et al. Am. J. Hum. Genet. 2016 May;98:801-17; Byers H et al. Eur. J. Hum. Genet. 2016 Nov;24:1591-1597; Lerner-Ellis J et al. J Cancer Res Clin Oncol, 2021 Mar;147:871-879). This mutation has also been reported in an individual diagnosed with grade 2 papillary serous cystadenocarcinoma, in a pre-menopausal breast cancer patient who underwent oophorectomy and was found to have serous tubal intraepithelial cancer, and in prostate cancer patients (Thompson E et al. PLoS One. 2013;8:e54772; Harvey LFB et al. J Minim Invasive Gynecol. 2017 Aug;[Epub ahead of print]; Nguyen-Dumont T et al. Int J Cancer, 2020 10;147:2142-2149). 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. - |
Pathogenic, criteria provided, single submitter | curation | Sema4, Sema4 | Mar 02, 2022 | - - |
Breast and/or ovarian cancer Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | CZECANCA consortium | Jun 11, 2019 | - - |
Malignant tumor of breast Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | Department of Pathology and Laboratory Medicine, Sinai Health System | - | The RAD51D p.Arg186X variant was identified in 7 of 15516 proband chromosomes (frequency: 0.00045) from individuals or families with breast and/or ovarian cancer or at high risk of ovarian cancer and was not identified in 7744 control chromosomes from healthy individuals (Loveday 2011, Song 20015, Thompson 2013, Keen-Kim 2017, Osher 2012). The variant was also identified in dbSNP (ID: rs387906843) as “With Pathogenic allele”, ClinVar (classified 5x as pathogenic by Ambry Genetics, Invitae, Counsyl, Color Genomics and GeneDx; classified as risk factor by OMIM), Clinvitae (same references as ClinVar), databases. The variant was not identified in the COSMIC database. The variant was identified in control databases in 8 of 275060 chromosomes at a frequency of 0.00003 in the following populations: Ashkenazi Jewish in 4 of 10036 chromosomes (freq. 0.0004); European non-Finnish in 4 of 125824 chromosomes (freq. 0.00003), increasing the likelihood that this may be a low frequency variant in certain populations of origin (Genome Aggregation Consortium Feb 27, 2017). This variant was identified in 2 Canadian individuals with ovarian cancer from the same family, both of whom demonstrated loss of wild-type allele in DNA extracted from tumour cells (Osher 2012). In a 3-generation pedigree segregating ovarian cancer and breast cancer this variant was found in 4 members of the same family (Loveday 2011). The proband had ovarian cancer at age 38; the variant was also confirmed in her sister who had breast cancer at age 39, and two aunts who had breast cancer at age 58 and age 53. Four other relatives on whom no molecular testing could be done died of ovarian cancer ranging in age from 49 to 65 years. Loss of function variants of the RAD51D gene are an established mechanism of disease in breast and ovarian cancer and is the type of variant expected to cause the disorder. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. - |
Ovarian neoplasm Pathogenic:1
Pathogenic, no assertion criteria provided | clinical testing | China-NCC-Department of Gynecologic Oncology, Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College | - | - - |
Hereditary breast ovarian cancer syndrome Pathogenic:1
Pathogenic, criteria provided, single submitter | clinical testing | Women's Health and Genetics/Laboratory Corporation of America, LabCorp | Sep 30, 2016 | Variant summary: The RAD51D c.556C>T (p.Arg186X) variant results in a premature termination codon, predicted to cause a truncated or absent RAD51D protein due to nonsense mediated decay, which are commonly known mechanisms for disease. A truncation located downstream of this position have been classified as pathogenic by our laboratory (e.g. p.Arg232X). Mutation taster predicts a damaging outcome for this variant. This variant was found in 6/115838 control chromosomes at a frequency of 0.0000518, which does not exceed the estimated maximal expected allele frequency of a pathogenic RAD51D variant (0.000125). It was reported in several breast and ovarian cancer patients indicating causality. In addition multiple clinical diagnostic laboratories classified this variant as pathogenic. Taken together, this variant is classified as pathogenic. - |
Computational scores
Source:
Splicing
Find out detailed SpliceAI scores and Pangolin per-transcript scores at