ClinVar Miner

Submissions for variant NM_005732.4(RAD50):c.1911T>A (p.Asp637Glu) (rs144749616)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 4
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000212911 SCV000149845 uncertain significance not provided 2014-02-13 criteria provided, single submitter clinical testing RAD50 has been only recently described in association with cancer predisposition and the risks are not well understood. This variant is denoted RAD50 c.1911T>A at the cDNA level, p.Asp637Glu (D637E) at the protein level, and results in the change of an Aspartic Acid to a Glutamic Acid (GAT>GAA). This variant has not, to our knowledge, been published in the literature as pathogenic or benign. RAD50 Asp637Glu was not observed at a significant allele frequency in the NHLBI Exome Sequencing Project or 1000 Genomes. This variant is a conservative substitution of one negative polar amino acid for another, altering a position that is well conserved throughout evolution and is located in a potential coiled coil region in the Zinc-hook domain (UniProt). In silico analyses are inconsistent with regard to the effect this variant may have on protein structure and function. On a molecular level, the impact of this missense variant on protein structure and function is not known and thus we consider this to be a variant of uncertain significance. Furthermore, based on the currently available information, cancer risks associated with this variant, and the RAD50 gene, remain unclear.
Ambry Genetics RCV000115936 SCV000186853 uncertain significance Hereditary cancer-predisposing syndrome 2020-07-07 criteria provided, single submitter clinical testing The p.D637E variant (also known as c.1911T>A), located in coding exon 12 of the RAD50 gene, results from a T to A substitution at nucleotide position 1911. The aspartic acid at codon 637 is replaced by glutamic acid, an amino acid with highly similar properties. In one study, this variant was reported in 0/1313 early-onset breast cancer cases and 1/1123 population controls (Damiola F et al. Breast Cancer Res. 2014 Jun;16:R58). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae RCV000115936 SCV000254883 uncertain significance Hereditary cancer-predisposing syndrome 2020-10-30 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glutamic acid at codon 637 of the RAD50 protein (p.Asp637Glu). The aspartic acid residue is moderately conserved and there is a small physicochemical difference between aspartic acid and glutamic acid. This variant is present in population databases (rs144749616, ExAC 0.007%). This variant has not been reported in the literature in individuals with RAD50-related disease. ClinVar contains an entry for this variant (Variation ID: 128000). 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: Tolerated; PolyPhen-2: Possibly Damaging; Align-GVGD: Class C0). 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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001290539 SCV001478596 likely benign not specified 2021-01-17 criteria provided, single submitter clinical testing Variant summary: RAD50 c.1911T>A (p.Asp637Glu) results in a conservative amino acid change located in the RAD50, zinc hook domain (IPR013134) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 5.6e-05 in 251332 control chromosomes, predominantly at a frequency of 0.00011 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 1.8 fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of Non-Finnish European origin. Although this variant has been reported in the literature, to our knowledge, no occurrence of c.1911T>A in individuals affected with Hereditary Breast And Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Two 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 likely benign.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.