Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV000563394 | SCV000668819 | uncertain significance | Hereditary cancer-predisposing syndrome | 2024-09-24 | criteria provided, single submitter | clinical testing | The c.681+5G>C intronic variant results from a G to C substitution 5 nucleotides after coding exon 7 in the BRCA2 gene. This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Quiles F et al. Breast Cancer Res Treat. 2016 Jan;155(2):253-60; Ambry internal data). However, RNA experiments for other alterations at this splice site have shown coding exon 7 splicing alterations to express an in-frame transcript, known as 6q39_8 in the literature (Ambry internal data). This transcript has been shown to be able to perform homology directed repair in protein functional studies at a near wild-type level (Mesman, RLS et al. Genet Med 2020 08;22(8):1355-1365). Since the abundance and functional activity of the 6q39_8 transcript is not clear, the clinical impact of this splicing variant is uncertain. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Labcorp Genetics |
RCV001867883 | SCV002294044 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2022-09-24 | criteria provided, single submitter | clinical testing | 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. 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 exon 8 skipping and introduces a premature termination codon (PMID: 26780556). The resulting mRNA is expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 483115). This variant has been observed in individual(s) with breast cancer (PMID: 26780556). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 8 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 may result in an absent or disrupted protein product. |