Total submissions: 6
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Gene |
RCV000212922 | SCV000149858 | uncertain significance | not provided | 2023-06-14 | criteria provided, single submitter | clinical testing | Variants in candidate genes are classified as variants of uncertain significance in accordance with ACMG guidelines (Richards et al., 2015); In silico analysis supports that this missense variant does not alter protein structure/function; Has not been previously published as pathogenic or benign to our knowledge; This variant is associated with the following publications: (PMID: 26689913, Duzkale2020[article]) |
Ambry Genetics | RCV000115949 | SCV000184404 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-03-22 | criteria provided, single submitter | clinical testing | The p.I947T variant (also known as c.2840T>C), located in coding exon 18 of the RAD50 gene, results from a T to C substitution at nucleotide position 2840. The isoleucine at codon 947 is replaced by threonine, 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 | RCV000115949 | SCV000254895 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-01-29 | criteria provided, single submitter | clinical testing | This sequence change replaces isoleucine, which is neutral and non-polar, with threonine, which is neutral and polar, at codon 947 of the RAD50 protein (p.Ile947Thr). This variant is present in population databases (rs150401251, gnomAD 0.01%). This missense change has been observed in individual(s) with lung adenocarcinoma (PMID: 26689913). ClinVar contains an entry for this variant (Variation ID: 128013). 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. |
Counsyl | RCV000410140 | SCV000488874 | uncertain significance | Nijmegen breakage syndrome-like disorder | 2016-07-09 | criteria provided, single submitter | clinical testing | |
Women's Health and Genetics/Laboratory Corporation of America, |
RCV001194193 | SCV001363538 | uncertain significance | not specified | 2023-10-10 | criteria provided, single submitter | clinical testing | Variant summary: RAD50 c.2840T>C (p.Ile947Thr) 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 6.5e-05 in 247912 control chromosomes, predominantly at a frequency of 0.00012 within the Non-Finnish European subpopulation in the gnomAD database. The observed variant frequency within Non-Finnish European control individuals in the gnomAD database is approximately 2-fold of the estimated maximal expected allele frequency for a pathogenic variant in RAD50 causing Hereditary Breast And Ovarian Cancer Syndrome phenotype (6.3e-05), suggesting that the variant could be a benign polymorphism found primarily in populations of Non-Finnish European origin. c.2840T>C has been reported in the literature in an individual affected with lung adenocarcinoma (Lu 2015), an individual with gastric cancer (Bruns_2022) and in an individual with an unspecified type of cancer from a cohort of patients who had a strong family history with at least two affected relatives (Sahin_2022). 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. The following publications have been ascertained in the context of this evaluation (PMID: 35250968, 26689913, 35089076). Four 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 VUS-possibly benign. |
Genome |
RCV000410140 | SCV002075111 | not provided | Nijmegen breakage syndrome-like disorder | no assertion provided | phenotyping only | Variant interpreted as Uncertain significance and reported on 03-25-2021 by Lab or GTR ID 239772. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant. |