Total submissions: 3
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Color Diagnostics, |
RCV000584318 | SCV000689004 | uncertain significance | Hereditary cancer-predisposing syndrome | 2020-06-10 | criteria provided, single submitter | clinical testing | This variant causes an A to G nucleotide substitution at the -2 position of intron 11 of the BRCA2 gene. This variant has not been reported in individuals affected with hereditary cancer in the literature although an exon 12 deletion has been reported in a breast/ovarian cancer patient (PMID: 30555256). Several lines of evidence suggest that deletion of exon 12 is tolerated in normal tissues. Alternative splicing of exon 12 was reported in multiple control samples (PMID: 10363970, 15026808, 19795481, 32046981, 32133419). A functional study reported that a similar canonical acceptor site variant (6842-1G>A with demonstrated in exon 12 skipping) retained protein function, as assayed by repair activity and BRCA2-null cell complementation studies, and failed to segregate with breast cancer in a family (PMID: 32046981). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). The available evidence is insufficient to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance. |
| Ambry Genetics | RCV000584318 | SCV002664995 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-01-28 | criteria provided, single submitter | clinical testing | The c.6842-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 11 in the BRCA2 gene. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. However, RNA studies have demonstrated that this alteration as well as close match alterations at this donor site result in an increase in a transcript predicted to lead to a protein with an in-frame deletion of coding exon 11 (also known as exon 12 in the literature; Ambry internal data; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). This exon may be clinically dispensable based on partially retained homology directed DNA repair activity (Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). In addition, the literature describes a patient with a splice variant causing coding exon 11 skipping variant in trans with a truncating BRCA2 variant in an individual without apparent Fanconi Anemia; although the degree of exon skipping is uncertain (Li L et al. Hum. Mutat., 2009 Nov;30:1543-50; Meulemans L et al. Cancer Res, 2020 04;80:1374-1386). Thus, the clinical impact of of this variant and its resulting protein cannot be predicted. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear. |
| Human Genome Sequencing Center Clinical Lab, |
RCV000709713 | SCV000839907 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 2 | 2017-01-18 | flagged submission | clinical testing | This c.6842-2A>G variant has not previously been reported in public databases, nor been observed in our patient cohort. This variant affects the invariant acceptor splice site of intron 11. While not validated for clinical use, one computer-based algorithm predicts this variant to activate a cryptic splice site within exon 12 at position c.6843_6844GA, which would result in the lost of nucleotide c.6842 to c.6844 and an inframe glycine deletion at position 2281 . It is thus interpreted as a likely pathogenic variant. |