ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.196G>A (p.Val66Met) (rs56026142)

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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 RCV000130161 SCV000184996 likely benign Hereditary cancer-predisposing syndrome 2018-09-23 criteria provided, single submitter clinical testing Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene;In silico models in agreement (benign)
Invitae RCV000858574 SCV000287700 benign not provided 2019-02-22 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000238834 SCV000297127 uncertain significance not specified 2015-07-30 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000343326 SCV000401971 uncertain significance Breast and Ovarian Cancer Susceptibility 2016-06-14 criteria provided, single submitter clinical testing
Counsyl RCV000225779 SCV000489108 uncertain significance Breast-ovarian cancer, familial 4 2016-08-22 criteria provided, single submitter clinical testing
GeneDx RCV000238834 SCV000515953 likely benign not specified 2017-10-11 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.
Color RCV000130161 SCV000686426 likely benign Hereditary cancer-predisposing syndrome 2015-11-16 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000238834 SCV000920125 likely benign not specified 2019-02-27 criteria provided, single submitter clinical testing Variant summary: RAD51D c.196G>A (p.Val66Met) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00032 in 277102 control chromosomes, predominantly at a frequency of 0.004 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 30 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 East Asian origin. Moreover, the variant was also reported in Japanese healthy controls with a frequency of 0.0116 that is approximately 90 fold higher than the estimated maximal expected allele frequency for a pathogenic RAD51D variant, further supporting that the variant is a benign polymorphism found primarily in populations of East Asian origin (HGVD). c.196G>A has been reported in the literature in individuals affected with cancer, including colorectal cancer and breast cancer (Hauke_2018, Yurgelun_2017, Lu_2015). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A co-occurrence with a pathogenic variant has been reported in our internal database (BRCA1 c.2800C>T, p.Gln934X), 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 from clinical diagnostic laboratories (evaluation after 2014) cite the variant as likely benign (4x) and as uncertain significance (3x). Based on the evidence outlined above, the variant was classified as likely benign.

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