Total submissions: 3
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001041383 | SCV001204995 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-04-19 | 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 839591). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change creates a premature translational stop signal (p.Gln202Lysfs*32) in the BRCA1 gene. Loss-of-function variants in BRCA1 are expected to be pathogenic (PMID: 20104584). However, an in-frame BRCA1 isoform lacking exons 8 and 9 (also known as exons 9 and 10) is highly expressed in blood from unaffected individuals and in normal breast tissue; this isoform may retain protein function and could functionally rescue loss-of-function variants within exons 8-9 (PMID: 24569164). |
Ambry Genetics | RCV002355002 | SCV002654892 | uncertain significance | Hereditary cancer-predisposing syndrome | 2021-10-06 | criteria provided, single submitter | clinical testing | The c.604delC pathogenic mutation, located in coding exon 8 of the BRCA1 gene, results from a deletion of one nucleotide at nucleotide position 604, causing a translational frameshift with a predicted alternate stop codon (p.Q202Kfs*32). Alterations that result in premature protein truncation are typically deleterious in nature. However, because this alteration occurs in one of the two exons that are absent in an in-frame, partially functional, naturally occurring isoform (Δ7_8 which is known in the literature as BRCA1 Δ9_10), it has an uncertain impact on pathogenicity (Colombo M et al. Hum. Mol. Genet. 2014 Jul;23:3666-80; Whiley PJ et al. Clin. Chem. 2014 Feb;60:341-52). As such, the clinical significance of this alteration remains unclear. |
Baylor Genetics | RCV003473624 | SCV004211719 | pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2021-11-23 | criteria provided, single submitter | clinical testing |