ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.270_271dup (p.Lys91fs) (rs753862052)

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Total submissions: 7
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000226442 SCV000287703 pathogenic Breast-ovarian cancer, familial 4 2020-10-23 criteria provided, single submitter clinical testing This sequence change creates a premature translational stop signal (p.Lys91Ilefs*13) in the RAD51D gene. It is expected to result in an absent or disrupted protein product. This variant is present in population databases (rs753862052, ExAC 0.1%). This variant has been observed in an individual with ovarian and breast cancer (PMID: 21822267), and an individual with male breast cancer (PMID: 28008555). ClinVar contains an entry for this variant (Variation ID: 239394). Loss-of-function variants in RAD51D are known to be pathogenic (PMID: 21822267). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000570770 SCV000663808 pathogenic Hereditary cancer-predisposing syndrome 2019-01-31 criteria provided, single submitter clinical testing The c.270_271dupTA pathogenic mutation, located in coding exon 4 of the RAD51D gene, results from a duplication of TA at nucleotide position 270, causing a translational frameshift with a predicted alternate stop codon (p.K91Ifs*13). This mutation has been detected in multiple ovarian cancer patients as well as male and female breast cancer patients (Loveday C et al. Nat. Genet. 2011 Sep;43:879-82; Frey MK et al. Gynecol. Oncol. 2015 Nov;139:211-5; Susswein LR et al. Genet. Med. 2016 Aug;18:823-32; Pritzlaff M et al. Breast Cancer Res. Treat. 2017 Feb;161:575-586; Sun J et al. Clin. Cancer Res. 2017 Oct;23:6113-6119; Hirasawa A et al. Oncotarget. 2017 Nov;8:112258-112267; Wang YA et al. BMC Cancer. 2018 Mar;18:315; Eoh KJ et al. Cancer Res Treat. 2018 Jul;50:917-925). 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.
Counsyl RCV000226442 SCV000677792 likely pathogenic Breast-ovarian cancer, familial 4 2017-05-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000570770 SCV000686437 pathogenic Hereditary cancer-predisposing syndrome 2021-02-16 criteria provided, single submitter clinical testing This variant inserts 2 nucleotides in exon 4 of the RAD51D gene, creating a frameshift and premature translation stop signal. This variant is expected to result in an absent or non-functional protein product. This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 21822267, 28008555, 29020732, 29348823, 32068069). This variant has been identified in 14/251448 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.
GeneDx RCV000657171 SCV000778892 pathogenic not provided 2017-11-15 criteria provided, single submitter clinical testing This duplication of 2 nucleotides is denoted RAD51D c.270_271dupTA at the cDNA level and p.Lys91IlefsX13 (K91IfsX13) at the protein level. The normal sequence, with the bases that are duplicated in brackets, is TTGA[dupTA]AACT. The duplication causes a frameshift, which changes a Lysine to an Isoleucine at codon 91, and creates a premature stop codon at position 13 of the new reading frame. This variant is predicted to cause loss of normal protein function through either protein truncation or nonsense-mediated mRNA decay. RAD51D 270_271dupTA has been observed in at least one woman with a personal history of both breast and ovarian cancer, one man with breast cancer, and one unaffected individual with a family history of breast and ovarian cancer (Loveday 2011, Frey 2015, Pritzlaff 2017). We consider this variant to be pathogenic.
Cancer Genomics Group,Japanese Foundation For Cancer Research RCV001030591 SCV001193728 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-05-01 criteria provided, single submitter research
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001030591 SCV001363871 pathogenic Hereditary breast and ovarian cancer syndrome 2021-06-21 criteria provided, single submitter clinical testing Variant summary: RAD51D c.270_271dupTA (p.Lys91IlefsX13) results in a premature termination codon, predicted to cause a truncation of the encoded protein or absence of the protein due to nonsense mediated decay, which are commonly known mechanisms for disease. The variant allele was found at a frequency of 6.3e-05 in 253126 control chromosomes, predominantly at a frequency of 0.00076 within the East Asian subpopulation in the gnomAD database. c.270_271dupTA has been reported in the literature in multiple individuals affected with Breast and Ovarian Cancer (example: Loveday_2011, Sun_2017, Zeng_2020). These data indicate that the variant is very likely to be associated with disease. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. In addition, a recent large case-control study evaluating breast cancer cases and controls and a large scale meta-analyses evaluating ovarian cancer cases and controls found a moderate risk association of RAD51D truncating variants with familial breast cancer (overall odds ratio (OR) =1.80, 95% Cis: 1.112.93, p=0.018) as well as with ovarian cancer (overall OR = 6.94, 95% CI: 5.109.44; p< 0.0001) (Dorling_2021, Suszynska_2020). Six other ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.

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