Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000219668 | SCV000274690 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-12-07 | criteria provided, single submitter | clinical testing | The p.R1069I variant (also known as c.3206G>T), located in coding exon 21 of the RAD50 gene, results from a G to T substitution at nucleotide position 3206. The arginine at codon 1069 is replaced by isoleucine, an amino acid with similar properties. This amino acid position is well 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 | RCV000219668 | SCV000753309 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-30 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with isoleucine, which is neutral and non-polar, at codon 1069 of the RAD50 protein (p.Arg1069Ile). This variant is present in population databases (rs769003601, gnomAD 0.02%). This variant has not been reported in the literature in individuals affected with RAD50-related conditions. ClinVar contains an entry for this variant (Variation ID: 230977). Advanced modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) performed at Invitae indicates that this missense variant is not expected to disrupt RAD50 protein function with a negative predictive value of 80%. 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. |
| Fulgent Genetics, |
RCV000765808 | SCV000897198 | uncertain significance | Nijmegen breakage syndrome-like disorder | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001375528 | SCV001572385 | uncertain significance | not specified | 2021-04-01 | criteria provided, single submitter | clinical testing | Variant summary: RAD50 c.3206G>T (p.Arg1069Ile) results in a non-conservative amino acid change in 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 2.8e-05 in 251086 control chromosomes, predominantly at a frequency of 0.0002 within the Latino subpopulation in the gnomAD database. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.3206G>T in individuals affected with Hereditary Breast and Ovarian Cancer Syndrome and no experimental evidence demonstrating its impact on protein function have been reported. Co-occurrences with another likely pathogenic variant has been reported ( CHEK2 c.349A>G, p.Arg117Gly) in our internal database. Three ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |
| Sema4, |
RCV000765808 | SCV002538498 | uncertain significance | Nijmegen breakage syndrome-like disorder | 2021-05-29 | criteria provided, single submitter | curation |