Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000582365 | SCV000688776 | uncertain significance | Hereditary cancer-predisposing syndrome | 2019-04-28 | criteria provided, single submitter | clinical testing | |
| Invitae | RCV001857061 | SCV002183580 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2024-01-25 | criteria provided, single submitter | clinical testing | This sequence change replaces valine, which is neutral and non-polar, with isoleucine, which is neutral and non-polar, at codon 959 of the BRCA2 protein (p.Val959Ile). This variant is not present in population databases (gnomAD no frequency). This missense change has been observed in individual(s) with clinical features of BRCA2-related conditions (PMID: 34326862). ClinVar contains an entry for this variant (Variation ID: 433773). 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 BRCA2 protein function with a negative predictive value of 95%. 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 | RCV000582365 | SCV002749544 | likely benign | Hereditary cancer-predisposing syndrome | 2021-12-22 | 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. |
| University of Washington Department of Laboratory Medicine, |
RCV000582365 | SCV003850198 | likely benign | Hereditary cancer-predisposing syndrome | 2023-03-23 | criteria provided, single submitter | curation | Missense variant in a coldspot region where missense variants are very unlikely to be pathogenic (PMID:31911673). |
| Department of Pathology and Laboratory Medicine, |
RCV000503350 | SCV000591831 | likely benign | Breast-ovarian cancer, familial, susceptibility to, 2 | no assertion criteria provided | clinical testing | The BRCA2 p.Val959Ile variant was not identified in the literature nor was it identified in the dbSNP, NHLBI Exome Sequencing Project (Exome Variant Server), HGMD, LOVD, COSMIC, UMD, ClinVar, or BIC databases. The p.Val959 residue is not conserved in mammals and the variant amino acid Ile is present in mouse, rat, cat, and dog, increasing the likelihood that this variant does not have clinical significance. In addition, computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) do not suggest a high likelihood of impact to the protein. However, this information is not predictive enough to rule out pathogenicity. In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as predicted benign. |