ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.983C>T (p.Thr328Ile) (rs138969595)

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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 RCV000129828 SCV000184643 likely benign Hereditary cancer-predisposing syndrome 2018-11-05 criteria provided, single submitter clinical testing Subpopulation frequency in support of benign classification;Other data supporting benign classification
GeneDx RCV000254688 SCV000211662 likely benign not specified 2017-08-07 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Counsyl RCV000411668 SCV000488575 uncertain significance Breast-ovarian cancer, familial 4 2016-06-09 criteria provided, single submitter clinical testing
Invitae RCV000411668 SCV000551327 likely benign Breast-ovarian cancer, familial 4 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000129828 SCV000902869 likely benign Hereditary cancer-predisposing syndrome 2016-04-28 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000859034 SCV001134809 likely benign not provided 2019-01-08 criteria provided, single submitter clinical testing
Mendelics RCV000411668 SCV001140402 likely benign Breast-ovarian cancer, familial 4 2019-05-28 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000254688 SCV001363868 benign not specified 2019-07-18 criteria provided, single submitter clinical testing Variant summary: RAD51D c.983C>T (p.Thr328Ile) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00011 in 282876 control chromosomes, predominantly at a frequency of 0.0012 within the African or African-American subpopulation in the gnomAD database, including 1 homozygotes. The observed variant frequency within African or African-American control individuals in the gnomAD database is approximately 10 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 African or African-American origin. The variant, c.983C>T, has been reported in the literature in individuals affected with Lynch syndromeassociated cancer and/or polyps (Yurgelun_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with a BRCA1 pathogenic variant has been reported (c.3598C>T, p.Gln1200X), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven ClinVar submissions (evaluation after 2014) cite the variant four times as likely benign and three times as uncertain significance. Based on the evidence outlined above, the variant was classified as benign.

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