Total submissions: 4
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000131286 | SCV000186256 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-03-09 | criteria provided, single submitter | clinical testing | The p.E1275G variant (also known as c.3824A>G), located in coding exon 25 of the RAD50 gene, results from an A to G substitution at nucleotide position 3824. The glutamic acid at codon 1275 is replaced by glycine, an amino acid with similar properties. This alteration was previously reported in at least one individual from a cohort of 278 BRCA1/2-negative individuals with early-onset breast cancer via multiplex panel testing of 22 cancer susceptibility genes (Maxwell KN et al. Genet Med, 2015 Aug;17:630-8). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be deleterious by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Invitae | RCV000131286 | SCV000628291 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-11-03 | criteria provided, single submitter | clinical testing | This sequence change replaces glutamic acid, which is acidic and polar, with glycine, which is neutral and non-polar, at codon 1275 of the RAD50 protein (p.Glu1275Gly). This variant is present in population databases (rs372924978, gnomAD 0.002%). This missense change has been observed in individual(s) with breast cancer (PMID: 25503501). ClinVar contains an entry for this variant (Variation ID: 142265). 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 expected to disrupt RAD50 protein function with a positive 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. |
| Baylor Genetics | RCV003467171 | SCV004207368 | uncertain significance | Nijmegen breakage syndrome-like disorder | 2023-07-21 | criteria provided, single submitter | clinical testing | |
| Women's Health and Genetics/Laboratory Corporation of America, |
RCV003479017 | SCV004223464 | uncertain significance | not specified | 2023-11-07 | criteria provided, single submitter | clinical testing | Variant summary: RAD50 c.3824A>G (p.Glu1275Gly) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 4e-06 in 251310 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3824A>G has been reported in the literature in at least one individual with early onset breast cancer, where it was described as a VUS (e.g. Maxwell_2015). This report does 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. The following publication has been ascertained in the context of this evaluation (PMID: 25503501). Two submitters have cited clinical-significance assessments for this variant to ClinVar after 2014. All submitters classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance. |