ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7806-2A>G (rs81002836)

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Total submissions: 14
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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 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 and ovarian cancer syndrome 2020-10-18 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 this variant induces altered splicing and may result in an absent or disrupted protein product. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals affected with breast/ovarian cancer and is considered a founder mutation in the Slovenian population (PMID: 10449599, 12461697, 23199084, 12461697, 18439106, 18783588, 21232165). ClinVar contains an entry for this variant (Variation ID: 52418). Studies have shown that this variant is associated with exon 17 skipping, which introduces a frameshift (PMID: 12461697, 10449599). 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 2019-01-02 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; however, in one quantitative RNA study, this transcript was present at relatively low levels in the patient-derived cells (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:). 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). Of note, this alteration is also designated as IVS16-2A>G in published literature. In addition to the clinical data and results from splicing assays presented in the literature, alterations that disrupt the canonical splice site are expected to cause aberrant splicing, resulting in an abnormal protein or a transcript that is subject to nonsense-mediated mRNA decay. As such, this alteration is classified 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 The variant disrupts a canonical splice site, and is therefore predicted to result in the loss of a functional protein. Found in at least one patient with expected phenotype for this gene, and not found in general population data.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077414 SCV000327739 pathogenic Breast-ovarian cancer, familial 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 Health, Inc RCV000131088 SCV000903528 pathogenic Hereditary cancer-predisposing syndrome 2019-01-15 criteria provided, single submitter clinical testing
Centre for Mendelian Genomics,University Medical Centre Ljubljana RCV000077414 SCV001366713 pathogenic Breast-ovarian cancer, familial 2 2016-01-01 criteria provided, single submitter clinical testing This variant was classified as: Pathogenic.
Human Genome Sequencing Center Clinical Lab, Baylor College of Medicine RCV000077414 SCV001434858 pathogenic Breast-ovarian cancer, familial 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 1 2020-04-02 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077414 SCV000109212 likely pathogenic Breast-ovarian cancer, familial 2 2007-08-10 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077414 SCV000147193 pathogenic Breast-ovarian cancer, familial 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 and 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 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.

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