Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000167368 | SCV000218220 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-07-15 | criteria provided, single submitter | clinical testing | The p.Q737E variant (also known as c.2209C>G), located in coding exon 14 of the RAD50 gene, results from a C to G substitution at nucleotide position 2209. The glutamine at codon 737 is replaced by glutamic acid, an amino acid with highly similar properties. This alteration was detected in a Korean ovarian cancer patient (Choi MC et al. Cancer Res Treat, 2020 Apr;52:634-644). This alteration was also identified in a cohort of patients diagnosed with biliary tract carcinoma undergoing multigene panel testing for hereditary cancer risk (Terashima T et al. Oncotarget, 2019 Oct;10:5949-5957). 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 | RCV000167368 | SCV000628195 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-11 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamine, which is neutral and polar, with glutamic acid, which is acidic and polar, at codon 737 of the RAD50 protein (p.Gln737Glu). This variant is present in population databases (rs549559726, gnomAD 0.07%). This missense change has been observed in individual(s) with biliary tract cancer and/or pancreatic cancer (PMID: 31666926, 36135357). ClinVar contains an entry for this variant (Variation ID: 187622). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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, |
RCV000764585 | SCV000895676 | uncertain significance | Nijmegen breakage syndrome-like disorder | 2018-10-31 | criteria provided, single submitter | clinical testing | |
| Cancer Genomics Group, |
RCV001030506 | SCV001193706 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2019-05-01 | criteria provided, single submitter | research | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV001194195 | SCV001363540 | likely benign | not specified | 2019-12-23 | criteria provided, single submitter | clinical testing | Variant summary: RAD50 c.2209C>G (p.Gln737Glu) results in a 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 is located close to a canonical splice site therefore could affect splicing: 5/5 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 5.3e-05 in 247246 control chromosomes, predominantly at a frequency of 0.00071 within the East Asian subpopulation in the gnomAD database. The observed variant frequencies within East Asian control individuals in the gnomAD database is approximately 11-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast and Ovarian Cancer phenotype (6.3e-05), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. In addition, in certain East Asian subpopulations the variant was reported with even higher frequencies, e.g. in the Koreans (0.0032; in gnomAD) and in the Japanese (0.0040; in the jMorp database), further supporting a benign role of the variant. The variant c.2209C>G has been reported in the literature in two Japanese individuals affected with biliary tract carcinoma (Terashima_2019), however without strong evidence for causality. 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, and all of them classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |