Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Invitae | RCV000198855 | SCV000254897 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-18 | criteria provided, single submitter | clinical testing | This sequence change replaces lysine, which is basic and polar, with arginine, which is basic and polar, at codon 108 of the RAD50 protein (p.Lys108Arg). This variant is present in population databases (rs542347773, gnomAD 0.07%). 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: 216628). 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. |
| Ambry Genetics | RCV000198855 | SCV000663597 | likely benign | Hereditary cancer-predisposing syndrome | 2024-04-25 | criteria provided, single submitter | clinical testing | This alteration is classified as likely benign based on a combination of the following: seen in unaffected individuals, population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity. |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV000780665 | SCV000918124 | likely benign | not specified | 2018-10-22 | criteria provided, single submitter | clinical testing | Variant summary: RAD50 c.323A>G (p.Lys108Arg) results in a conservative amino acid change located in the Rad50/SbcC-type AAA domain 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 5.1e-05 in 277040 control chromosomes, exclusively within the East Asian subpopulation at a frequency of 0.00074 in the gnomAD database. The observed variant frequency within East Asian control individuals is approximately 12-fold above 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. c.323A>G has been reported in the literature in an individual with a family history of Hereditary Breast and Ovarian Cancer (Sung_2017). 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. Two clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation and both classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as likely benign. |
| Laboratory of Molecular Epidemiology of Birth Defects, |
RCV003153473 | SCV003843700 | likely pathogenic | Ovarian cancer | 2022-01-01 | criteria provided, single submitter | clinical testing |