Submissions for variant NM_000059.4(BRCA2):c.7976+5G>A

dbSNP: rs786201180

Total submissions: 8

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000162937	SCV000213424	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-25	criteria provided, single submitter	clinical testing	The c.7976+5G>A intronic pathogenic mutation results from a G to A substitution 5 nucleotides after coding exon 16 in the BRCA2 gene. This alteration has been identified in several Asian cohorts being tested for BRCA1 and BRCA2 mutations (Bhaskaran SP et al. Int. J. Cancer, 2019 Aug;145:962-973; Wong MS et al. Mol. Cell, 2018 09;71:1012-1026.e3; Kwong A et al. J Mol Diagn, 2016 07;18:580-94; Kwong A et al. J. Med. Genet., 2016 Jan;53:15-23). This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is well conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice donor site. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data; Wong MS et al. Mol. Cell, 2018 09;71:1012-1026.e3). A close match alteration at the same nucleotide position, BRCA2 c.7976+5G>T was shown to produce the same splice defect in multiple unrelated carriers tested at different Spanish institutions (Montalban G et al. Hum. Mutat., 2018 Sep;39:1155-1160). Based on the majority of evidence available to date, this alteration is considered a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258212	SCV000327778	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000637349	SCV000695111	likely pathogenic	Hereditary breast ovarian cancer syndrome	2022-02-14	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.7976+5G>A alters a conserved nucleotide in intron 17, located close to the splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. The 5' splice site of BRCA2 intron 17 has a non-canonical sequence, with a cytosine at the +2 position (CAG/GCAAGT), therefore computational tools were not able to predict the impact of the variant on normal splicing, however a publication reported experimental evidence demonstrating that the variant resulted in complete skipping of exon 17 in a minigene assay (Wong_2018). The skipping of exon 17 is predicted to result in the in-frame deletion of 57 amino acids, which was demonstrated to result in a protein product deficient in HDR activity (PMID: 18451181). The variant was absent in 251100 control chromosomes (gnomAD). The variant, c.7976+5G>A, has been reported in the literature in at least one Chinese individual affected with breast cancer (Kwong_2013, Rebbeck_2018, Bhaskaran_2019). Six other submitters have provided clinical-significance assessments for this variant in ClinVar after 2014, and classified the variant as pathogenic (n=2) / likely pathogenic (n=2) or VUS (n=2). Based on the evidence outlined above, the variant was classified as likely pathogenic.
Labcorp Genetics (formerly Invitae), Labcorp	RCV000637349	SCV000758802	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-12-07	criteria provided, single submitter	clinical testing	This sequence change falls in intron 17 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. RNA analysis indicates that this variant induces altered splicing and likely results in a shortened protein product. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with breast cancer (PMID: 26187060). This variant is also known as IVS17+5G>A. ClinVar contains an entry for this variant (Variation ID: 183947). 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 17, but is expected to preserve the integrity of the reading-frame (PMID: 30174293). This variant disrupts the c.7976+5G nucleotide in the BRCA2 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 29969168). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000586885	SCV000889144	likely pathogenic	not provided	2024-05-14	criteria provided, single submitter	clinical testing	The BRCA2 c.7976+5G>A variant has been reported in the published literature in individuals affected with breast cancer (PMID: 26187060 (2015)) and premature ovarian insufficiency (PMID: 36732629 (2023)). It is reported to interfere with normal splicing and cause exon 17 skipping (PMID: 30174293 (2018)). This variant has not been reported in large, multi-ethnic general populations (Genome Aggregation Database, http://gnomad.broadinstitute.org). Based on the available information, this variant is classified as likely pathogenic.
Color Diagnostics, LLC DBA Color Health	RCV000162937	SCV000906566	likely pathogenic	Hereditary cancer-predisposing syndrome	2020-03-26	criteria provided, single submitter	clinical testing	This variant causes a G to A nucleotide substitution at the +5 position of intron 17 of the BRCA2 gene. This variant is also known as IVS17+5G>A in the literature. A minigene splicing assay found that this variant resulted in the skipping of exon 17 (PMID: 30174293). This variant has been observed in an individual at-risk for familial breast and/or ovarian cancer (PMID: 26187060). A different c.7976+5G>T variant has been shown by RNA studies to cause in-frame skipping of exon 17 (PMID: 29969168, 31191615), resulting in a non-functional protein (PMID: 15695382, 18451181). The c.7976+5G>T variant also has been observed in multiple individuals affected with breast and/or ovarian cancer (PMID: 29969168). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Likely Pathogenic.
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496302	SCV000587924	uncertain significance	not specified	2014-01-31	flagged submission	research
Counsyl	RCV000258212	SCV000786313	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2018-04-13	flagged submission	clinical testing