ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5406+4_5406+7del (rs1555575073)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000637486 SCV000758947 likely pathogenic Hereditary breast and ovarian cancer syndrome 2019-03-12 criteria provided, single submitter clinical testing 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, but it affects a nucleotide within the consensus splice site of the intron. This variant is not present in population databases (ExAC no frequency). This variant has been observed in two family members from a family affected with breast and ovarian cancer (PMID: 30374176). ClinVar contains an entry for this variant (Variation ID: 531285). Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant may disrupt protein function and/or mRNA splicing (PMID: 30374176, 30209399). A different variant affecting this consensus splice site (c.5406+5G>T) has been determined to be pathogenic (PMID: 12491487, 26681312, Invitae). This suggests that this nucleotide is important for normal RNA splicing, and that other variants at this position may also be pathogenic. 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.
University of Washington Department of Laboratory Medicine, University of Washington RCV000637486 SCV000886449 pathogenic Hereditary breast and 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 1; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research

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