ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.796C>T (p.Arg266Cys) (rs587781813)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130084 SCV000184912 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-30 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000255993 SCV000321930 uncertain significance not provided 2018-07-26 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.796C>T at the cDNA level, p.Arg266Cys (R266C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant has been reported in at least one woman with ovarian cancer and another with breast cancer (Thompson 2013, Hauke 2018). RAD51D Arg266Cys was observed at an allele frequency of 0.08% (24/30,782) in individuals of South Asian ancestry in large population cohorts (Lek 2016). This variant is located in the RAD51C binding domain (Miller 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, it is unclear whether RAD51D Arg266Cys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000411407 SCV000489353 uncertain significance Breast-ovarian cancer, familial 4 2016-09-27 criteria provided, single submitter clinical testing
Invitae RCV000411407 SCV000551380 likely benign Breast-ovarian cancer, familial 4 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000130084 SCV000686488 uncertain significance Hereditary cancer-predisposing syndrome 2020-03-09 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000255993 SCV000806588 uncertain significance not provided 2017-10-02 criteria provided, single submitter clinical testing
GeneKor MSA RCV000130084 SCV000822184 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000255993 SCV000888611 uncertain significance not provided 2019-06-12 criteria provided, single submitter clinical testing
Mendelics RCV000411407 SCV001140411 uncertain significance Breast-ovarian cancer, familial 4 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193713 SCV001362752 likely benign not specified 2019-05-23 criteria provided, single submitter clinical testing Variant summary: RAD51D c.796C>T (p.Arg266Cys) results in a non-conservative amino acid change located in the DNA recombination and repair protein RecA-like, ATP-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00018 in 251416 control chromosomes, predominantly at a frequency of 0.00085 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 7 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer phenotype (0.00013), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.796C>T, has been reported in the literature in individuals affected with breast and/or ovarian cancer (Thompson_2013, Lu_2015, Konstanta_2018, Krivokuca_2019). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Eight ClinVar submissions from other clinical diagnostic laboratories (evaluation after 2014) cite the variant eight times as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign.
GenomeConnect, ClinGen RCV000255993 SCV000986823 not provided not provided no assertion provided phenotyping only Variant interpretted as Uncertain significance and reported on 05/07/2018 by GTR ID Credit Valley Hospital Department of Laboratory Medicine. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.

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