ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.3253A>G (p.Ile1085Val) (rs143189763)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115953 SCV000185694 likely benign Hereditary cancer-predisposing syndrome 2017-07-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,Other data supporting benign classification
GeneDx RCV000235202 SCV000149862 uncertain significance not provided 2015-11-13 criteria provided, single submitter clinical testing RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.3253A>G at the cDNA level, p.Ile1085Val (I1085V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Ile1085Val was observed with an allele frequency of 0.3% (15/4404) in African Americans in the NHLBI Exome Sequencing Project (ESP), not frequent enough to be considered a polymorphism. This variant is a conservative substitution of one neutral non-polar amino acid for another, altering a position that is well conserved throughout evolution and is not located in a known functional domain (UniProt). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear.
Integrated Genetics/Laboratory Corporation of America RCV000781784 SCV000920110 benign not specified 2018-05-18 criteria provided, single submitter clinical testing Variant summary: RAD50 c.3253A>G (p.Ile1085Val) results in a 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 observed variant frequency within African control individuals in the gnomAD database is approximately 50 fold above 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 African origin. c.3253A>G has been reported in the literature but does 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. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 with conflicting interpretations including VUS (1x), likely benign (1x), and benign (1x). Based on the evidence outlined above, the variant was classified as benign.
Invitae RCV000115953 SCV000253466 benign Hereditary cancer-predisposing syndrome 2018-01-03 criteria provided, single submitter clinical testing

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