Submissions for variant NM_000059.4(BRCA2):c.425+3A>G

dbSNP: rs932657676

Total submissions: 6

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Women's Health and Genetics/Laboratory Corporation of America, LabCorp	RCV000589863	SCV000694755	uncertain significance	not provided	2016-03-28	criteria provided, single submitter	clinical testing	Variant Summary: The variant of interest is located at a conserved intronic position, not widely known to affect splicing, with 2/5 in silico programs via Alamut predicting significant effect on splicing, although these predictions have yet to be functionally assessed. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP), nor, has it been, to our knowledge, reported in affected individuals via publications and/or reputable databases/clinical laboratories. Therefore, taking all available lines of evidence into consideration, the variant of interest is classified as a "Variant of Uncertain Significance (VUS)," until additional information becomes available.
Ambry Genetics	RCV001022141	SCV001183840	uncertain significance	Hereditary cancer-predisposing syndrome	2024-06-12	criteria provided, single submitter	clinical testing	The c.425+3A>G intronic variant results from an A to G substitution 3 nucleotides after coding exon 3 in the BRCA2 gene. 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. RNA studies have demonstrated that this alteration results in abnormal splicing in the set of samples tested (Ambry internal data). RNA studies of a close-match alteration, BRCA2 c.425G>T, have demonstrated that it results in complete abnormal splicing in the set of samples tested (Ambry internal data; Brandão R et al. Breast Cancer Res. Treat. 2011 Oct;129(3):971-82; Nix P et al. Fam Cancer, 2021 Jan). BRCA2 c.425G>T, which has the same splicing profile as this alteration (Ambry internal data), was able to rescue the growth defect in BRCA2-null mouse embryonic stem cells and these surviving cells maintained partial activity in a homology directed DNA repair functional assay (Mesman R et al. Genet Med 2020 Aug;22(8):1355-1365). BRCA2 c.425G>T was also identified in patients who collectively have a phenotype that is not consistent with a high risk BRCA2 pathogenic variant (Nix P et al. Fam Cancer, 2021 Jan). Based on the available evidence, the clinical significance of this variant remains unclear.
Labcorp Genetics (formerly Invitae), Labcorp	RCV001233483	SCV001406080	uncertain significance	Hereditary breast ovarian cancer syndrome	2023-05-04	criteria provided, single submitter	clinical testing	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. Variants that disrupt the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may disrupt the consensus splice site. ClinVar contains an entry for this variant (Variation ID: 495460). This variant has not been reported in the literature in individuals affected with BRCA2-related conditions. This variant is not present in population databases (gnomAD no frequency). This sequence change falls in intron 4 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.
Baylor Genetics	RCV003459452	SCV004213667	uncertain significance	Familial cancer of breast	2023-08-15	criteria provided, single submitter	clinical testing
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV000589863	SCV001740696	uncertain significance	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV000589863	SCV001958533	uncertain significance	not provided		no assertion criteria provided	clinical testing