ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.751A>G (p.Ile251Val) (rs540273429)

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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 RCV000129767 SCV000184576 uncertain significance Hereditary cancer-predisposing syndrome 2017-06-20 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000129767 SCV000904087 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-14 criteria provided, single submitter clinical testing
GeneDx RCV000236753 SCV000293833 uncertain significance not provided 2017-03-24 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.751A>G at the cDNA level, p.Ile251Val (I251V) at the protein level, and results in the change of an Isoleucine to a Valine (ATA>GTA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Ile251Val was not observed in large population cohorts (Lek 2016, The 1000 Genomes Consortium 2015, NHLBI Exome Sequencing Project). Since Isoleucine and Valine share similar properties, this is considered a conservative amino acid substitution. RAD51D Ile251Val occurs at a position where amino acids with properties similar to Isoleucine are tolerated across species and is located in the RAD51C binding domain (Miller 2004). In silico analyses predict that this variant is unlikely to alter protein structure or function. Based on currently available evidence, it is unclear whether RAD51D Ile251Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000542443 SCV000651777 uncertain significance Breast-ovarian cancer, familial 4 2018-01-19 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 251 of the RAD51D protein (p.Ile251Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with RAD51D-related disease. ClinVar contains an entry for this variant (Variation ID: 141300). 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 valine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. 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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