Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Gene |
RCV000656992 | SCV000149806 | uncertain significance | not provided | 2017-07-06 | criteria provided, single submitter | clinical testing | This variant is denoted XRCC2 c.773G>A at the cDNA level, p.Arg258His (R258H) at the protein level, and results in the change of an Arginine to a Histidine (CGT>CAT). This variant has not, to our knowledge, been published in the literature as a germline variant; however, it has been reported as a somatic variant in the NCI-60 cancer cell line database (Reinhold 2014). XRCC2 Arg258His was observed at an allele frequency of 0.01% (1/10,306) in individuals of African American ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Arginine and Histidine share similar properties, this is considered a conservative amino acid substitution. XRCC2 Arg258His occurs at a position that is not conserved and is not located in a known functional domain. In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available evidence, it is unclear whether XRCC2 Arg258His is a pathogenic variant or a benign variant. We consider it to be a variant of uncertain significance. |
| Labcorp Genetics |
RCV000656992 | SCV000550360 | uncertain significance | not provided | 2024-11-19 | criteria provided, single submitter | clinical testing | This sequence change replaces arginine, which is basic and polar, with histidine, which is basic and polar, at codon 258 of the XRCC2 protein (p.Arg258His). This variant is present in population databases (rs149186933, gnomAD 0.03%). This variant has not been reported in the literature in individuals affected with XRCC2-related conditions. ClinVar contains an entry for this variant (Variation ID: 127963). Invitae Evidence Modeling of protein sequence and biophysical properties (such as structural, functional, and spatial information, amino acid conservation, physicochemical variation, residue mobility, and thermodynamic stability) indicates that this missense variant is not expected to disrupt XRCC2 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 | RCV000567423 | SCV000675845 | likely benign | Hereditary cancer-predisposing syndrome | 2024-01-09 | 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. |
| Sema4, |
RCV000567423 | SCV002538381 | uncertain significance | Hereditary cancer-predisposing syndrome | 2022-01-09 | criteria provided, single submitter | curation | |
| Fulgent Genetics, |
RCV005031609 | SCV005667300 | uncertain significance | Fanconi anemia complementation group U; Spermatogenic failures 50; Premature ovarian failure 17 | 2024-06-17 | criteria provided, single submitter | clinical testing |