ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1094G>A (p.Arg365Gln) (rs146370443)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000115926 SCV000183886 likely benign Hereditary cancer-predisposing syndrome 2018-01-29 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Other data supporting benign classification
Fulgent Genetics,Fulgent Genetics RCV000515281 SCV000611508 uncertain significance Nijmegen breakage syndrome-like disorder 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000212907 SCV000149835 uncertain significance not provided 2014-01-20 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.1094G>A at the cDNA level, p.Arg365Gln (R365Q) at the protein level, and results in the change of an Arginine to a Glutamine (CGA>CAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Arg365Gln was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a semi-conservative substitution of a positive polar amino acid for a neutral polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. In silico analyses predict this variant to have a benign effect 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.
GeneKor MSA RCV000115926 SCV000822142 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000115926 SCV000254872 uncertain significance Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces arginine with glutamine at codon 365 of the RAD50 protein (p.Arg365Gln). The arginine residue is moderately conserved and there is a small physicochemical difference between arginine and glutamine. This variant is present in population databases (rs146370443, ExAC 0.06%). This variant has been reported in individuals affected with breast cancer (PMID: 24894818) and ovarian cancer (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 127990). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.

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