Total submissions: 4
Submitter | RCV | SCV | Clinical significance | Condition | Last evaluated | Review status | Method | Comment |
---|---|---|---|---|---|---|---|---|
Invitae | RCV001237400 | SCV001410157 | uncertain significance | Hereditary breast ovarian cancer syndrome | 2023-12-30 | criteria provided, single submitter | clinical testing | This sequence change affects a donor splice site in intron 8 of 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). This variant is not present in population databases (gnomAD no frequency). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 963383). Studies have shown disruption of this splice site is associated with skipping of exon 8-9 and skipping of exon 8, but one or more of the resulting mRNA isoform(s) may be naturally occurring (PMID: 24569164; Invitae). 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. |
Baylor Genetics | RCV003473814 | SCV004212705 | likely pathogenic | Breast-ovarian cancer, familial, susceptibility to, 1 | 2023-10-18 | criteria provided, single submitter | clinical testing | |
Department of Pathology and Laboratory Medicine, |
RCV001358105 | SCV001553756 | pathogenic | not provided | no assertion criteria provided | clinical testing | The BRCA1 c.593+1G>A variant was not identified in the literature nor was it identified in the dbSNP, ClinVar, LOVD 3.0, databases. The variant was identified in UMD-LSDB (2x reported as class 5, casual).The variant was not identified in the following control databases: the Exome Aggregation Consortium (August 8th 2016) or the Genome Aggregation Database (Feb 27, 2017). The c.593+1G>A variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 3 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information this variant meets our laboratory’s criteria to be classified as pathogenic. | |
Laboratory for Genotyping Development, |
RCV003166473 | SCV002758210 | pathogenic | Gastric cancer | 2021-07-01 | no assertion criteria provided | research |