ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1277A>G (p.Gln426Arg) (rs145428112)

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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 RCV000115929 SCV000186121 uncertain significance Hereditary cancer-predisposing syndrome 2017-07-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or Conflicting Evidence
Fulgent Genetics,Fulgent Genetics RCV000515382 SCV000611509 uncertain significance Nijmegen breakage syndrome-like disorder 2017-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000212909 SCV000149838 uncertain significance not provided 2014-02-17 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.1277A>G at the cDNA level, p.Gln426Arg (Q426R) at the protein level, and results in the change of a Glutamine to an Arginine (CAA>CGA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Gln426Arg has not been observed at significant allele frequency in the NHLBI Exome Sequencing Project. This variant is a semi-conservative substitution in which a a neutral polar amino acid is replaced with a positive polar one, altering a position that is well conserved throughout evolution and is not located in a known functional domain. Multiple in silico algorithms predict that this variant may be damaging to 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 RCV000115929 SCV000822143 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Invitae RCV000115929 SCV000254876 uncertain significance Hereditary cancer-predisposing syndrome 2019-01-08 criteria provided, single submitter clinical testing This sequence change replaces glutamine with arginine at codon 426 of the RAD50 protein (p.Gln426Arg). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and arginine. This variant is present in population databases (rs145428112, ExAC 0.03%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 127993). Algorithms developed to predict the effect of missense changes on protein structure and function are either unavailable or do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C0"). 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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