Submissions for variant NM_000059.4(BRCA2):c.682-1G>C

dbSNP: rs81002831

Total submissions: 5

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000215277	SCV000274334	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-06-23	criteria provided, single submitter	clinical testing	The c.682-1G>C intronic variant results from a G to C substitution one nucleotide upstream from coding exon 8 of the BRCA2 gene. This alteration (designated as IVS8-1G>C) was identified in a Sri Lankan patient diagnosed with both breast and ovarian cancer at age 46, who also had a family history of breast cancer (De Silva S et al. Exp Ther Med. 2011 Nov; 2(6):1163-1170). This variant was previously reported in the SNPDatabase as rs81002831, but was absent from population-based cohorts in the NHLBI Exome Sequencing Project (ESP) and 1000 Genomes Project databases. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 300000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved in available vertebrate species. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site; however, direct evidence is unavailable. A third model predicts that this alteration will weaken the native splice acceptor site (Mucaki EJ et al. Hum. Mutat. 2011 Jul; 32(7):735-42). Alterations that disrupt the canonical splice acceptor site are typically deleterious in nature (ACMG Recommendations for Standards for Interpretation and Reporting of Sequence Variations. Revision 2007. Genet Med. 2008; 10:294). As such, the c.682-1G>C variant is classified as likely pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000758938	SCV000887896	pathogenic	not provided	2018-06-21	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000496656	SCV001586456	pathogenic	Hereditary breast ovarian cancer syndrome	2023-09-12	criteria provided, single submitter	clinical testing	Disruption of this splice site has been observed in individual(s) with breast cancer, lymphoma, male breast cancer, and/or ovarian cancer (PMID: 22977638, 24123850, 29176636). For these reasons, this variant has been classified as Pathogenic. Studies have shown that disruption of this splice site alters mRNA splicing and is expected to lead to the loss of protein expression (PMID: 24123850, 30883759). ClinVar contains an entry for this variant (Variation ID: 52198). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 8 of the BRCA2 gene. RNA analysis indicates that disruption of this splice site induces altered splicing and may result in an absent or disrupted protein product.
Breast Cancer Information Core (BIC) (BRCA2)	RCV000114011	SCV000147479	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2004-02-20	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000496656	SCV000587562	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research