Total submissions: 5
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000561223 | SCV000668747 | uncertain significance | Hereditary cancer-predisposing syndrome | 2023-05-22 | criteria provided, single submitter | clinical testing | The p.V151I variant (also known as c.451G>A), located in coding exon 4 of the BRCA2 gene, results from a G to A substitution at nucleotide position 451. The valine at codon 151 is replaced by isoleucine, an amino acid with highly similar properties. A minigene assay demonstrated that this alteration results in skipping of coding exon 4 in over 89% of transcripts (Fraile-Bethencourt E et al. J Pathol, 2019 08;248:409-420); however RNA studies have demonstrated that this alteration does not result in abnormal splicing in the set of samples tested (Ambry internal data). This amino acid position is not 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. |
| Labcorp Genetics |
RCV000685146 | SCV000812619 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2024-10-22 | 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 151 of the BRCA2 protein (p.Val151Ile). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. ClinVar contains an entry for this variant (Variation ID: 37908). 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 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. |
| Gene |
RCV002281724 | SCV002571273 | uncertain significance | not provided | 2023-03-03 | criteria provided, single submitter | clinical testing | Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports that this missense variant does not alter protein structure/function; Published functional studies using a minigene assay demonstrate aberrant splicing and predict a truncated protein product (Fraile-Bethencourt et al., 2019); Also known as 679G>A; This variant is associated with the following publications: (PMID: 32623769, 30883759) |
| Prevention |
RCV004532444 | SCV004114519 | uncertain significance | BRCA2-related disorder | 2022-10-24 | criteria provided, single submitter | clinical testing | The BRCA2 c.451G>A variant is predicted to result in the amino acid substitution p.Val151Ile. To our knowledge, this variant (referred to as 679G>A using legacy nomenclature) has not been reported in the literature in association with BRCA2-related disease. Results from a minigene assay suggest that this variant predominantly results in skipping of exon 5 and occasionally both exons 5 and 6 (Fraile-Bethencourt et al. 2019. PubMed ID: 30883759); however even the wild type minigene construct had both of these events and it is unclear if the results from these experiments accurately represent in vivo splicing. Computational splicing prediction programs predict that this variant would likely not have an impact on splicing (Alamut Visual Plus v1.6.1). This variant has not been reported in a large population database (http://gnomad.broadinstitute.org), indicating this variant is rare. In ClinVar, this variant is interpreted as uncertain (https://www.ncbi.nlm.nih.gov/clinvar/variation/37908). At this time, the clinical significance of this variant is uncertain due to the absence of conclusive functional and genetic evidence. |
| Sharing Clinical Reports Project |
RCV000031489 | SCV000054094 | uncertain significance | Breast-ovarian cancer, familial, susceptibility to, 2 | 2009-12-23 | no assertion criteria provided | clinical testing |