ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.835G>A (p.Asp279Asn) (rs765271127)

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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 RCV000213661 SCV000275805 uncertain significance Hereditary cancer-predisposing syndrome 2017-08-30 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
Color RCV000213661 SCV000686492 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
GeneDx RCV000484011 SCV000569682 uncertain significance not provided 2016-03-21 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.835G>A at the cDNA level, p.Asp279Asn (D279N) at the protein level, and results in the change of an Aspartic Acid to an Asparagine (GAC>AAC). This variant has been reported in at least one individual with a Lynch-syndrome associated tumor and/or colon polyps (Yurgelun 2015). RAD51D Asp279Asn was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, suggesting it is not a common benign variant in these populations. Since Aspartic Acid and Asparagine differ in some properties, this is considered a semi-conservative amino acid substitution. RAD51D Asp279Asn occurs at a position that is not conserved and is located in the ATPase domain (Kim 2011). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether RAD51D Asp279Asn is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000649693 SCV000771525 uncertain significance Breast-ovarian cancer, familial 4 2018-10-16 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with asparagine at codon 279 of the RAD51D protein (p.Asp279Asn). The aspartic acid residue is weakly conserved and there is a small physicochemical difference between aspartic acid and asparagine. This variant is present in population databases (rs765271127, ExAC 0.02%). This variant has been reported in an individual affected with Lynch syndrome associated cancer and/or colorectal polyps (PMID: 25980754). ClinVar contains an entry for this variant (Variation ID: 231837). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but 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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