ClinVar Miner

Submissions for variant NM_002878.3(RAD51D):c.131G>C (p.Gly44Ala) (rs374730714)

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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 RCV000574341 SCV000667158 uncertain significance Hereditary cancer-predisposing syndrome 2017-10-10 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000478788 SCV000566457 uncertain significance not provided 2016-09-21 criteria provided, single submitter clinical testing This variant is denoted RAD51D c.131G>C at the cDNA level, p.Gly44Ala (G44A) at the protein level, and results in the change of a Glycine to an Alanine (GGC>GCC). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD51D Gly44Ala 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 Glycine and Alanine share similar properties, this is considered a conservative amino acid substitution. RAD51D Gly44Ala occurs at a position that is not conserved and is located in the region that preferentially binds ssDNA (Kim 2011, UniProt). 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 Gly44Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000781804 SCV000920135 uncertain significance not specified 2018-12-07 criteria provided, single submitter clinical testing Variant summary: The variant, RAD51D c.131G>C (p.Gly44Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 251812 control chromosomes (gnomAD and Song _2015). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.131G>C, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Song _2015). However, this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000463087 SCV000551326 uncertain significance Breast-ovarian cancer, familial 4 2018-11-08 criteria provided, single submitter clinical testing This sequence change replaces glycine with alanine at codon 44 of the RAD51D protein (p.Gly44Ala). The glycine residue is moderately conserved and there is a small physicochemical difference between glycine and alanine. This variant is not present in population databases (ExAC no frequency). This variant has been reported in an individual affected with ovarian cancer (PMID: 26261251). ClinVar contains an entry for this variant (Variation ID: 410546). 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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