Submissions for variant NM_007294.4(BRCA1):c.5406+4_5406+7del

dbSNP: rs1555575073

Total submissions: 3

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637486	SCV000758947	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-03-27	criteria provided, single submitter	clinical testing	In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic. This variant disrupts the c.5406+5G nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 12491487, 26681312, 30209399; Invitae). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant results in skipping of exon 22 and introduces a new termination codon (PMID: 31843900). However the mRNA is not expected to undergo nonsense-mediated decay. ClinVar contains an entry for this variant (Variation ID: 531285). This variant has been observed in individual(s) with breast cancer and/or ovarian cancer (PMID: 30374176). This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 21 of the BRCA1 gene. It does not directly change the encoded amino acid sequence of the BRCA1 protein. RNA analysis indicates that this variant induces altered splicing and likely disrupts the C-terminus of the protein.
University of Washington Department of Laboratory Medicine, University of Washington	RCV000637486	SCV000886449	pathogenic	Hereditary breast ovarian cancer syndrome	2018-07-27	criteria provided, single submitter	research	The BRCA1 variant designated as NM_007294.3:c.5406+4_5406+7delAGTA is classified as pathogenic. This variant has not been reported in public population databases. Cosegregation analysis of one observed family using analyze.myvariant.org (Rañola et al, 2018, PMID:28965303) and yields a likelihood ratio of 7.46 to 1 (Thompson et al, 2003, PMID:2900794), indicating this allele is more likely to cause cancer in the family. Computational programs predicted that this variant would lead to elimination of a strong donor site. RNA studies of whole blood sample provided evidence that this variant leads to skipping of exon 22 (del 74bp in message, stop at codon 1804 of 1864) and corresponds to the entirety of BRCA1 transcript produced by the mutant allele. Bayesian analysis integrating all of this data (Tavtigian et al, 2018, PMID: 29300386) gives about 99% probability of pathogenicity, which is consistent with a classification of pathogenic. This variant is expected to alter BRCA1 function and increase risks related to BRCA1-associated cancers. This analysis was performed in conjunction with the family studies project as part of the University of Washington Find My Variant Study.
King Laboratory, University of Washington	RCV001171439	SCV001251350	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1; Hereditary breast ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research