ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.509T>C (p.Val170Ala) (rs370679685)

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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 RCV000220610 SCV000275054 uncertain significance Hereditary cancer-predisposing syndrome 2017-12-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000220610 SCV000691343 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-18 criteria provided, single submitter clinical testing
GeneDx RCV000236493 SCV000293406 uncertain significance not provided 2015-11-13 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.509T>C at the cDNA level, p.Val170Ala (V170A) at the protein level, and results in the change of a Valine to an Alanine (GTG>GCG). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Val170Ala was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project. Since Valine and Alanine share similar properties, this is considered a conservative amino acid substitution. RAD51D Val170Ala occurs at a position where amino acids with properties similar to Valine are tolerated across species 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 Val170Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000698370 SCV000827030 uncertain significance Breast-ovarian cancer, familial 4 2018-08-28 criteria provided, single submitter clinical testing This sequence change replaces valine with alanine at codon 170 of the RAD51D protein (p.Val170Ala). The valine residue is moderately conserved and there is a small physicochemical difference between valine and alanine. This variant is present in population databases (rs370679685, ExAC 0.01%). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 231261). 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 alanine 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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