Submissions for variant NM_000059.4(BRCA2):c.7806-2A>G

dbSNP: rs81002836

Total submissions: 22

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA)	RCV000077414	SCV001161563	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-06-18	reviewed by expert panel	curation	IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 5 based on posterior probability = 0.998459
Invitae	RCV000045321	SCV000073334	pathogenic	Hereditary breast ovarian cancer syndrome	2024-01-28	criteria provided, single submitter	clinical testing	This sequence change affects an acceptor splice site in intron 16 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. This variant is not present in population databases (gnomAD no frequency). Disruption of this splice site has been observed in individual(s) with breast/ovarian cancer (PMID: 10449599, 12461697, 18439106, 18783588, 21232165, 23199084). It is commonly reported in individuals of Slovenian ancestry (PMID: 10449599, 12461697, 18439106, 18783588, 21232165, 23199084). ClinVar contains an entry for this variant (Variation ID: 52418). Studies have shown that disruption of this splice site results in activation of a cryptic splice site and introduces a premature termination codon (PMID: 10449599, 12461697; Invitae). The resulting mRNA is expected to undergo nonsense-mediated decay. For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics	RCV000131088	SCV000186018	pathogenic	Hereditary cancer-predisposing syndrome	2024-01-02	criteria provided, single submitter	clinical testing	The c.7806-2A>G intronic pathogenic mutation results from an A to G substitution two nucleotides upstream from coding exon 16 in the BRCA2 gene. This alteration has been reported in splicing studies from both minigene and RT-PCR from patient cells to result in multiple aberrant transcripts including a majority of transcripts derived from the use of a cryptic acceptor site 20 nucleotides downstream in exon 17 (coding exon 16) leading to a predicted frameshift (Krajc M et al. Eur. J. Hum. Genet. 2002 Dec;10:879-82; Houdayer C et al. Hum. Mutat. 2012 Aug;33:1228-38; Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13(3):e1006691; Gelli E et al. Cancers (Basel) 2019 Mar;11; Ambry internal data). This alteration has been described as a Slovenian founder mutation and has been identified in hereditary breast and ovarian cancer patients, male breast cancer patients, and familial pancreatic cancer patients (Santarosa M et al. Int. J. Cancer. 1999 Sep;83:5-9; Krajc M et al. Eur. J. Hum. Genet. 2002 Dec;10:879-82; Miolo G et al. BMC Cancer. 2006 Jun;6:156; Murphy KM et al. Cancer Res. 2002 Jul;62:3789-93; Miolo G et al. BMC Cancer. 2006 Jun;6:156; Besic N et al. Genet. Test. 2008 Jun;12:203-9). In addition, a high ratio of breast cancer versus ovarian cancer (relative risk: 16.33) has been noted in families harboring this alteration (Krajc M et al. BMC Med. Genet. 2008;9:83). This alteration was classified as pathogenic in a multifactorial model of variant interpretation that incorporates co-segregation, family history, co-occurrence, tumor pathology, and case-control data (Parsons MT et al. Hum Mutat. 2019 Sep;40(9):1557-1578). Of note, this alteration is also designated as IVS16-2A>G in published literature. This variant is considered to be rare based on population cohorts in the Genome Aggregation Database (gnomAD). This nucleotide position is highly conserved in available vertebrate species. In silico splice site analysis predicts that this alteration will weaken the native splice acceptor site and will result in the creation or strengthening of a novel splice acceptor site. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV001281729	SCV000296681	pathogenic	not provided	2020-01-29	criteria provided, single submitter	clinical testing	This variant is located in a canonical splice-acceptor site and interferes with normal BRCA2 mRNA splicing. In the published literature, this variant has been reported in individuals with hereditary breast and/or ovarian cancer (PMID: 29446198 (2018), 10449599 (1999)). Additionally, it has been described as a founder variant in Slovenian breast cancer populations (PMID: 24312913 (2013), PMID: 21232165 (2011), 12461697 (2002)). Functional studies have confirmed that this variant leads to aberrant splicing (PMID: 28339459 (2017), 10449599 (1999)). 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 pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge	RCV000077414	SCV000327739	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2015-10-02	criteria provided, single submitter	clinical testing
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000414989	SCV000492750	pathogenic	Neoplasm of ovary	2015-10-06	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000131088	SCV000903528	pathogenic	Hereditary cancer-predisposing syndrome	2023-04-18	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 16 of the BRCA2 gene. RNA studies have detected aberrant splicing products in carrier RNA (PMID: 10449599, 12461697, 22505045, 30832263) and in a minigene splicing assay (PMID: 28339459) that include out-of-frame and in-frame splicing products. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 individuals affected with breast and/or ovarian cancer and 1 individual affected with pancreatic cancer (PMID: 10449599, 12097290, 16764716, 18439106, 29470806, 33891299) and has a segregation likelihood ratio for pathogenicity of 7.1109 (PMID: 31131967). Haplotype analyses suggest that this variant is a founder mutation in Slovenia and Italy (PMID: 12461697, 18439106, 26852130). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Centre for Mendelian Genomics, University Medical Centre Ljubljana	RCV000077414	SCV001366713	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-12-09	criteria provided, single submitter	research	PVS1, PS3, PS4_STR, PM2_SUP
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine	RCV000077414	SCV001434858	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2019-02-28	criteria provided, single submitter	clinical testing	This c.7806-2A>G variant in the BRCA2 gene disrupts the canonical splice donor site in intron 16 and is predicted to result in abnormal mRNA splicing. This variant is absent from large databases of genetic variation in the general population. This variant has been reported in multiple patients with breast, ovarian and pancreatic cancers (PMID 10449599, 12097290, 16764716, 18783588). Therefore, this c.7806-2A>G variant in the BRCA2 gene is classified as pathogenic.
Department of Molecular Diagnostics, Institute of Oncology Ljubljana	RCV001310176	SCV001499771	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 1	2020-04-02	criteria provided, single submitter	clinical testing
GeneDx	RCV001281729	SCV002097424	pathogenic	not provided	2022-02-02	criteria provided, single submitter	clinical testing	Canonical splice site variant the produces multiple transcripts, leading to an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product (Santarosa 1999, Krajc 2002, Fraile-Bethencourt 2017, Gelli 2019); Observed in individuals with a personal or family history consistent with pathogenic variants in this gene, and is a founder variant in the Slovenian and North-Eastern Italian populations (Santarosa 1999, Krajc 2002, Marroni 2004, Besic 2008, Stegel 2011, Cini 2016); Not observed at significant frequency in large population cohorts (gnomAD); Truncating variants in this gene are considered pathogenic by a well-established clinical consortium and/or database; Also known as 8034-2A>G; This variant is associated with the following publications: (PMID: 19818148, 20104584, 26295337, 29907814, 12461697, 15340362, 22505045, 22923021, 25525159, 10449599, 10923033, 28339459, 24156927, 26852130, 22984553, 17301269, 16764716, 21232165, 18439106, 18783588, 23397983, 12097290, 24312913, 23199084, 25186627, 29470806, 29446198, 34399810, 33891299, 31131967, 12228710, 30832263, 30613976, 31360904)
Sema4, Sema4	RCV000131088	SCV002531886	pathogenic	Hereditary cancer-predisposing syndrome	2022-02-10	criteria provided, single submitter	curation
CeGaT Center for Human Genetics Tuebingen	RCV001281729	SCV002563165	pathogenic	not provided	2020-12-01	criteria provided, single submitter	clinical testing
Baylor Genetics	RCV003473407	SCV004210452	pathogenic	Familial cancer of breast	2022-11-14	criteria provided, single submitter	clinical testing
All of Us Research Program, National Institutes of Health	RCV000077414	SCV004830246	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2023-12-18	criteria provided, single submitter	clinical testing	This variant causes an A to G nucleotide substitution at the -2 position of intron 16 of the BRCA2 gene. RNA studies have detected aberrant splicing products in carrier RNA (PMID: 10449599, 12461697, 22505045, 30832263) and in a minigene splicing assay (PMID: 28339459) that include out-of-frame and in-frame splicing products. To our knowledge, functional studies have not been reported for this variant. This variant has been reported in at least 10 individuals affected with breast and/or ovarian cancer and 1 individual affected with pancreatic cancer (PMID: 10449599, 12097290, 16764716, 18439106, 29470806, 33891299) and has a segregation likelihood ratio for pathogenicity of 7.1109 (PMID: 31131967). Haplotype analyses suggest that this variant is a founder mutation in Slovenia and Italy (PMID: 12461697, 18439106, 26852130). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Loss of BRCA2 function is a known mechanism of disease (clinicalgenome.org). Based on the available evidence, this variant is classified as Pathogenic.
Sharing Clinical Reports Project (SCRP)	RCV000077414	SCV000109212	likely pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2007-08-10	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000077414	SCV000147193	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Research Molecular Genetics Laboratory, Women's College Hospital, University of Toronto	RCV000045321	SCV000587912	pathogenic	Hereditary breast ovarian cancer syndrome	2014-01-31	no assertion criteria provided	research
Department of Pathology and Laboratory Medicine, Sinai Health System	RCV000077414	SCV000592147	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2		no assertion criteria provided	clinical testing	The c.7806-2A>G variant was identified in 14 of 872 proband chromosomes (frequency: 0.016) from individuals or families with hereditary breast or ovarian cancer (Santarosa 1999, Novakovic 2012). The variant was also identified in dbSNP (ID: rs81002836) “With likely pathogenic allele”, HGMD, the ClinVar database (classified as a Pathogenic/Likely pathogenic variant by the Sharing Clinical Reports Project, derived from Myriad reports), GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (1X, classified as “pathogenic” by a clinical laboratory), the BIC database (5X with “pending” clinical importance), and UMD (5X as a causal variant).The c.7806-2A>G variant is predicted to cause abnormal splicing because the nucleotide substitution occurs in the invariant region of the splice consensus sequence. In addition, 5 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing. Also, mini-gene splicing assays show the variant to have a severe impact on splicing (Houdayer 2012). In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.
Genome Diagnostics Laboratory, University Medical Center Utrecht	RCV001281729	SCV001927448	pathogenic	not provided		no assertion criteria provided	clinical testing
Joint Genome Diagnostic Labs from Nijmegen and Maastricht, Radboudumc and MUMC+	RCV001281729	SCV001959599	pathogenic	not provided		no assertion criteria provided	clinical testing
BRCAlab, Lund University	RCV000077414	SCV002588915	pathogenic	Breast-ovarian cancer, familial, susceptibility to, 2	2022-08-26	no assertion criteria provided	clinical testing