ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.745A>G (p.Asn249Asp) (rs730881949)

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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 RCV000562724 SCV000663832 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Color RCV000562724 SCV000691362 uncertain significance Hereditary cancer-predisposing syndrome 2018-09-21 criteria provided, single submitter clinical testing
GeneDx RCV000160951 SCV000211658 uncertain significance not provided 2015-06-15 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.745A>G at the cDNA level, p.Asn249Asp (N249D) at the protein level, and results in the change of an Asparagine to an Aspartic Acid (AAC>GAC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Asn249Asp was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Asparagine and Aspartic Acid differ in some properties, this is considered a semi-conservative amino acid substitution. RAD51D Asn249Asp occurs at a position that is conserved across species and is located in the ATPase domain (Kim 2011). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether RAD51D Asn249Asp is pathogenic or benign. We consider it to be a variant of uncertain significance.
Invitae RCV000475132 SCV000551322 uncertain significance Breast-ovarian cancer, familial 4 2018-02-09 criteria provided, single submitter clinical testing This sequence change replaces asparagine with aspartic acid at codon 249 of the RAD51D protein (p.Asn249Asp). The asparagine residue is highly conserved and there is a small physicochemical difference between asparagine and aspartic acid. This variant is present in population databases (rs730881949, ExAC 0.003%) but has not been reported in the literature in individuals with a RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 182862). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Probably Damaging"; Align-GVGD: "Class C15"). In summary, this variant is a rare missense change with uncertain impact on protein function. There is no indication that it causes disease, but the available evidence is currently insufficient to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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