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

dbSNP: rs1567804153

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	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
Ambry Genetics	RCV004951408	SCV005549972	uncertain significance	Hereditary cancer-predisposing syndrome	2024-07-01	criteria provided, single submitter	clinical testing	The c.593+1G>A intronic variant results from a G to A substitution one nucleotide after coding exon 7 of the BRCA1 gene. In BRCA1, several naturally occurring in-frame minor isoforms have been reported. Alterations in consensus splice sites that are skipped in these naturally occurring in-frame minor isoforms have an uncertain impact on pathogenicity. The c.594-1G intronic splice site is one such nucleotide, located in an exon(7)/intron(7) boundary that is skipped in one (BRCA1 delta 9-10, also known as CDS7_8del) of the reported in-frame minor isoforms. The BRCA1 delta 9-10 in-frame isoform is one amongst the predominantly expressed minor isoforms in healthy individuals (Colombo M et al. Hum Mol Genet. 2014; 23:3666-80). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site; however, direct evidence is insufficient at this time (Ambry internal data). Based upon the available evidence, the clinical significance of this variant remains unclear.
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