Total submissions: 2
| Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
|---|---|---|---|---|---|---|---|---|
| Ambry Genetics | RCV002417178 | SCV002719445 | likely pathogenic | Hereditary cancer-predisposing syndrome | 2017-11-28 | criteria provided, single submitter | clinical testing | The c.2001+2T>C intronic variant results from a T to C substitution two nucleotides after coding exon 10 in the BARD1 gene. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice donor site; however, direct evidence is unavailable. Alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or transcript; however, the mRNA may escape nonsense mediated decay (NMD) since premature termination codons located either in the last exon or within 50-55 nucleotides upstream of the 3'-most exon-exon junction usually fail to elicit NMD (Maquat LE et al. Nat. Rev. Mol. Cell Biol. 2004 Feb; 5(2):89-99). However, the c.2001+2T>C alteration is located 5’ to the BARD1 BRCT domain (residues 568-777), which has been described as similar to those of the BRCA1 gene, and may be important for ligand binding (Birrane G et al. Biochemistry 2007 Jul; 46(26):7706-12). Further, an additional pathogenic mutation in the BARD1 gene, c.2148_2149delCA, is located 3’ to this alteration and has been described in a patient diagnosed with fallopian tube cancer at age 53 (Walsh, T el al. Proc Natl Acad Sci U S A. 2011 Nov 1;108(44):18032-7). Based on the available evidence, c.2001+2T>C is interpreted as likely pathogenic. |
| Quest Diagnostics Nichols Institute San Juan Capistrano | RCV003477000 | SCV004222388 | uncertain significance | not provided | 2022-12-16 | criteria provided, single submitter | clinical testing | This variant disrupts a canonical splice-donor site in the second to last exon, but may not result in nonsense mediated decay. To the best of our knowledge, the variant has not been reported in the published literature. The frequency of this variant in the general population, 0.000004 (1/251366 chromosomes, http://gnomad.broadinstitute.org), is uninformative in assessment of its pathogenicity. Based on the available information, we are unable to determine the clinical significance of this variant. |