Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000215910 | SCV000275920 | uncertain significance | Hereditary cancer-predisposing syndrome | 2015-05-27 | criteria provided, single submitter | clinical testing | The c.7976+4A>G intronic variant (also known as IVS17+4A>G) results from an A to G substitution 4 nucleotides after coding exon 16 in the BRCA2 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 150000 alleles tested) in our clinical cohort. This nucleotide position is well conserved in available vertebrate species. The ESEfinder in silico splicing model predicts a weakening in the native splice donor site efficiency while the BDGP tool does not produce a prediction for the native splice donor site. Since supporting evidence is limited at this time, the clinical significance of c.7976+4A>G remains unclear. |
| Labcorp Genetics |
RCV003644943 | SCV004463029 | pathogenic | Hereditary breast ovarian cancer syndrome | 2023-08-04 | criteria provided, single submitter | clinical testing | Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 17, but is expected to preserve the integrity of the reading-frame (Invitae). ClinVar contains an entry for this variant (Variation ID: 231922). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 17 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. For these reasons, this variant has been classified as Pathogenic. This variant disrupts a region of the BRCA2 protein in which other variant(s) (p.Leu2653Pro) have been determined to be pathogenic (PMID: 22678057, 29061967). This suggests that this is a clinically significant region of the protein, and that variants that disrupt it are likely to be disease-causing. |