ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.280A>C (p.Ile94Leu) (rs28903085)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000193160 SCV000149857 likely benign not specified 2014-02-25 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.
Ambry Genetics RCV000115948 SCV000172767 benign Hereditary cancer-predisposing syndrome 2014-11-20 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000193160 SCV000248649 likely benign not specified 2015-12-11 criteria provided, single submitter clinical testing
Invitae RCV000857578 SCV000262389 benign not provided 2019-03-06 criteria provided, single submitter clinical testing
Counsyl RCV000410963 SCV000488743 likely benign Nijmegen breakage syndrome-like disorder 2016-09-30 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000193160 SCV000698652 likely benign not specified 2019-01-15 criteria provided, single submitter clinical testing Variant summary: The variant, RAD50 c.280A>C (p.Ile94Leu) results in a conservative amino acid change located in the Rad50/SbcC-type AAA domain of 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 0.0034 in 280914 control chromosomes, including 5 homozygotes, predominantly at a frequency of 0.0061 within the South Asian subpopulation in the gnomAD database. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 98-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. The variant, c.280A>C, has been reported in the literature in individuals with a personal/family history of breast cancer, but was also found in controls (Tommiska_2006, Heikkinen_2003, Guacci_2018). 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. Five other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign(X1) / likely benign (X4). Based on the evidence outlined above, the variant was classified as likely benign.
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000410963 SCV000745438 likely benign Nijmegen breakage syndrome-like disorder 2016-06-15 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,VU University Medical Center Amsterdam RCV000410963 SCV000745944 likely benign Nijmegen breakage syndrome-like disorder 2017-04-25 no assertion criteria provided clinical testing

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