ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.919G>A (p.Glu307Lys) (rs115031549)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115821 SCV000185235 likely benign Hereditary cancer-predisposing syndrome 2017-08-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Subpopulation frequency in support of benign classification
Color RCV000115821 SCV000910718 benign Hereditary cancer-predisposing syndrome 2015-11-13 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000656966 SCV000859940 uncertain significance not provided 2018-03-09 criteria provided, single submitter clinical testing
GeneDx RCV000656966 SCV000149730 uncertain significance not provided 2018-08-13 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.919G>A at the cDNA level, p.Glu307Lys (E307K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). This variant was observed in at least two women with a personal history of breast cancer and a family history of breast or ovarian cancer (Tung 2015). RAD51D Glu307Lys was observed at an allele frequency of 0.29% (70/24,038) in individuals of African 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 that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether RAD51D Glu307Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000212975 SCV000918142 benign not specified 2018-07-31 criteria provided, single submitter clinical testing Variant summary: RAD51D c.919G>A (p.Glu307Lys) results in a conservative amino acid change located in the DNA recombination and repair protein Rad51-like, C-terminal domain of the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant was found in 78/277234 control chromosomes in gnomAD, but was observed primarily in the African subpopulation (70/24038 control chromosomes). The frequency within the African control individuals is more than 23-fold above the estimated maximal expected allele frequency for a pathogenic variant in RAD51D causing Hereditary Breast and Ovarian Cancer phenotype (0.00013). In addition, this variant has been found in 21/2559 African American women who are 70 years old or older and are cancer-free. These evidence strongly suggests that the variant is a benign polymorphism found primarily in populations of African origin. c.919G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer without strong evidence for causality. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Four clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting assessments including uncertain significance (2x) and likely benign (2x). Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000230920 SCV000287733 likely benign Breast-ovarian cancer, familial 4 2018-01-04 criteria provided, single submitter clinical testing
Mendelics RCV000709428 SCV000839170 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212975 SCV000602170 uncertain significance not specified 2016-11-28 criteria provided, single submitter clinical testing

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