ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.593+1G>A

dbSNP: rs1567804153
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Total submissions: 4
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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, Sinai Health System 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, RIKEN RCV003166473 SCV002758210 pathogenic Gastric cancer 2021-07-01 no assertion criteria provided research

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