Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000165841 | SCV000216589 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-07-27 | criteria provided, single submitter | clinical testing | The p.I698V variant (also known as c.2092A>G), located in coding exon 13 of the RAD50 gene, results from an A to G substitution at nucleotide position 2092. The isoleucine at codon 698 is replaced by valine, an amino acid with highly similar properties. 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 | RCV000165841 | SCV000628185 | likely benign | Hereditary cancer-predisposing syndrome | 2023-12-17 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003155098 | SCV003844475 | uncertain significance | not specified | 2023-02-09 | criteria provided, single submitter | clinical testing | Variant summary: RAD50 c.2092A>G (p.Ile698Val) results in a conservative amino acid change located in the zinc hook domain (IPR013134) of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251300 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2092A>G has been reported in the literature in individuals affected with or at high risk for Hereditary Breast and Ovarian Cancer Syndrome (e.g. Shalabi_2021, Nunziato_2022), however these reports did not provide supporting evidence for causality. In a recent large study evaluating breast cancer cases and controls in the Breast Cancer Association Consortium (BCAC), the variant was reported in 2/60466 cases, and was not found in 53461 controls (Dorling_2021, reported through LOVD). Therefore, these reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014. One laboratory classified the variant as likely benign, and one laboratory classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |