Submissions for variant NM_000059.4(BRCA2):c.8331+3A>C

gnomAD frequency: 0.00002  dbSNP: rs876659382

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000219350	SCV000275772	uncertain significance	Hereditary cancer-predisposing syndrome	2022-10-25	criteria provided, single submitter	clinical testing	The c.8331+3A>C intronic variant (also known as 8559+3A>C) results from an A to C substitution 3 nucleotides after coding exon 17 in the BRCA2 gene. 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 an incomplete splice defect; the clinical impact of this abnormal splicing is unknown at this time (Ambry internal data; Casadei S et al. Proc. Natl. Acad. Sci. U.S.A. 2019 116(52): 26798–26807). Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Invitae	RCV000230039	SCV000283339	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-10-04	criteria provided, single submitter	clinical testing	This sequence change falls in intron 18 of the BRCA2 gene. It does not directly change the encoded amino acid sequence of the BRCA2 protein. It affects a nucleotide within the consensus splice site. This variant is not present in population databases (gnomAD no frequency). This variant has been observed in individual(s) with hereditary breast and/or ovarian cancer (PMID: 31843900). ClinVar contains an entry for this variant (Variation ID: 231812). Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Studies have shown that this variant is associated with altered splicing resulting in unknown protein product impact (PMID: 31843900; 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.
Color Diagnostics, LLC DBA Color Health	RCV000219350	SCV000683957	uncertain significance	Hereditary cancer-predisposing syndrome	2021-11-17	criteria provided, single submitter	clinical testing	This variant causes an A to C nucleotide substitution at the +3 position of intron 18 of the BRCA2 gene. Splice site prediction tools predict that this variant may have a significant impact on RNA splicing. An RNA study has reported that this variant results in two aberrant mRNA transcripts with premature truncations in the coding sequence that are predicted to trigger nonsense-mediated decay, however, the extent of this splicing defect is partial and some full-length transcript is still produced (PMID: 31843900). This variant has not been reported in individuals affected with hereditary cancer in the literature. This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Although there is a suspicion that this variant may be associated with disease, additional studies are necessary to determine the role of this variant in disease conclusively. Therefore, this variant is classified as a Variant of Uncertain Significance.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV001192648	SCV001360903	uncertain significance	not specified	2019-09-23	criteria provided, single submitter	clinical testing	Variant summary: BRCA2 c.8331+3A>C alters a conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. Several computational tools predict a significant impact on normal splicing: Three predict the variant weakens a 5 prime donor site. Two predict the variant abolishes a 5 prime splicing donor site. However, these predictions have yet to be confirmed by functional studies. The variant was absent in 245066 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8331+3A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Three clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
GeneDx	RCV001530678	SCV001745570	uncertain significance	not provided	2022-07-18	criteria provided, single submitter	clinical testing	Published functional studies are inconclusive: both wild type and aberrant transcript observed (Casadei et al., 2019); Not observed at significant frequency in large population cohorts (gnomAD); In silico analysis supports a deleterious effect on splicing; Also known as BRCA2 8559+3A>C; This variant is associated with the following publications: (PMID: 31843900)
Fulgent Genetics, Fulgent Genetics	RCV002485423	SCV002786241	uncertain significance	Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 2; Fanconi anemia complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer, susceptibility to, 2; Glioma susceptibility 3	2022-03-27	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000238614	SCV004830349	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-01	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000238614	SCV000297566	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2009-05-05	no assertion criteria provided	clinical testing
King Laboratory, University of Washington	RCV001171452	SCV001251363	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2; Hereditary breast ovarian cancer syndrome	2019-09-01	no assertion criteria provided	research