Submissions for variant NM_000059.4(BRCA2):c.8332-2A>G

dbSNP: rs587782774

Total submissions: 12

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Ambry Genetics	RCV000132304	SCV000187389	likely pathogenic	Hereditary cancer-predisposing syndrome	2016-05-11	criteria provided, single submitter	clinical testing	The c.8332-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 18 in the BRCA2 gene. This variant was not reported in population based cohorts in the following databases: Database of Single Nucleotide Polymorphisms (dbSNP), NHLBI Exome Sequencing Project (ESP), and 1000 Genomes Project. In the ESP, this variant was not observed in 6503 samples (13006 alleles) with coverage at this position. To date, this alteration has been detected with an allele frequency of approximately 0.001% (greater than 225000 alleles tested) in our clinical cohort. This nucleotide position is highly conserved on sequence alignment. 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. 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.8332-2A>G variant is classified as likely pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000258406	SCV000327874	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Counsyl	RCV000258406	SCV000677762	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2017-02-14	criteria provided, single submitter	clinical testing
KCCC/NGS Laboratory, Kuwait Cancer Control Center	RCV000258406	SCV003932763	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-06-06	criteria provided, single submitter	clinical testing	The c.8332-2A>G intronic variant results from an A to G substitution two nucleotides upstream from coding exon 18 in the BRCA2 gene. This nucleotide position is highly conserved on sequence alignment. Using the BDGP and ESEfinder splice site prediction tools, this alteration is predicted to abolish the native splice acceptor site. 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). In-silico prediction show pathogenic computational verdict based on 6 pathogenic predictions from BayesDel_addAF, DANN, EIGEN, FATHMM-MKL, MutationTaster and scSNV-Splicing vs no benign predictions. ClinVar classifies this variant as Pathogenic, rated 2 stars, with 5 submissions and no conflicts. Therefore, the c.8332-2A>G variant is classified as pathogenic.
Baylor Genetics	RCV003474788	SCV004210498	likely pathogenic	Familial cancer of breast	2022-09-07	criteria provided, single submitter	clinical testing
Labcorp Genetics (formerly Invitae), Labcorp	RCV000503891	SCV004297185	likely pathogenic	Hereditary breast ovarian cancer syndrome	2023-04-26	criteria provided, single submitter	clinical testing	ClinVar contains an entry for this variant (Variation ID: 142861). Disruption of this splice site has been observed in individual(s) with breast and/or ovarian cancer (PMID: 29446198, 31343793). This variant is not present in population databases (gnomAD no frequency). This sequence change affects an acceptor splice site in intron 18 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. Studies have shown that disruption of this splice site results in partial deletion of exon 19 and skipping of exon 19 and introduces a premature termination codon (PMID: 21735045, 31343793). The resulting mRNA is expected to undergo nonsense-mediated decay. 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.
GeneDx	RCV001528892	SCV005396444	likely pathogenic	not provided	2024-05-08	criteria provided, single submitter	clinical testing	Canonical splice site variant demonstrated to result in a null allele in a gene for which loss of function is a known mechanism of disease (PMID: 31343793); Published functional study demonstrates inability to rescue cell viability in a complementation assay (PMID: 32398771); Not observed at significant frequency in large population cohorts (gnomAD); Also known as 8560-2A>G; This variant is associated with the following publications: (PMID: 28152038, 29446198, 31343793, 12228710, 32398771)
Molecular Diagnostics Laboratory, Catalan Institute of Oncology	RCV000132304	SCV005901866	likely pathogenic	Hereditary cancer-predisposing syndrome	2024-11-26	criteria provided, single submitter	clinical testing	PVS1 (RNA), PM2_Supporting c.8332-2A>G, located in a canonic splicing site of the BRCA2 gene, is predicted to alter splicing. Studies have shown that disruption of this splice site results in partial deletion of exon 19 and skipping of exon 19 and introduces a premature termination codon (r.[8332_8345del, r.8332_8487del]; p.[Ile2778Tyrfs*15, p.Ile2778_Gln2829del]) (PMID: 31343793) (PVS1(RNA). It is not present in the population database gnomAD v2.1.1, non cancer dataset (PM2_supporting). To our knowledge, functional studies have not been reported for this variant. In addition, the variant has been identified in the ClinVar database (6x pathogenic, 4x likely pathogenic), in the LOVD database (8x pathogenic) and BRCA Exchange database, (‘not yet reviewed’).Based on currently available information, the variant c.8332-2A>G is classified as a likely pathogenic variant according to ClinGen- BRCA1 and BRCA2 Guidelines version 1.0.0.
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV001353698	SCV000592183	pathogenic	Malignant tumor of breast		no assertion criteria provided	clinical testing	The c.8332-2A>G variant has not been previously identified in the literature nor by our laboratory and is of the type which is expected to cause the disorder. The c.8332-2A>G variant is located in the 3' splice region, and is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant -1 and -2 positions of the splice consensus sequence. In summary, based on the information above this variant is Pathogenic.
Hereditary Cancer Genetics group, Vall d'Hebron Institute of Oncology	RCV000503891	SCV000916371	pathogenic	Hereditary breast ovarian cancer syndrome	2019-03-01	no assertion criteria provided	research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen	RCV001528892	SCV001741404	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001528892	SCV001955283	pathogenic	not provided		no assertion criteria provided	clinical testing