ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.517-2A>G (rs81002858)

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Total submissions: 16
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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) RCV000077347 SCV001161557 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 = 0.999418
Invitae RCV000044589 SCV000072602 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-27 criteria provided, single submitter clinical testing This sequence change affects an acceptor splice site in intron 6 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 several individuals affected with breast or ovarian cancer (PMID: 14647210, 24728189, 26681682, 27836010). ClinVar contains an entry for this variant (Variation ID: 51801). Experimental studies have shown that this variant disrupts mRNA splicing and is expected to lead to the loss of protein expression (PMID: 22505045, 30883759). For these reasons, this variant has been classified as Pathogenic.
Ambry Genetics RCV000162897 SCV000213384 likely pathogenic Hereditary cancer-predisposing syndrome 2020-03-23 criteria provided, single submitter clinical testing The c.517-2A>G intronic variant results from an A to G substitution 2 nucleotides upstream from coding exon 6 in the BRCA2 gene. In one case report, this variant was reported in homozygous state in a 5-year-old boy with mixed Fanconi anemia phenotype (Leach M et al. Practical Flow Cytometry in Hematology: 100 worked examples. 321-324; 2015). This alteration has also been reported in conjunction with a truncating BRCA2 mutation in an individual with Fanconi anemia; however, the phase of these alterations (whether in cis or in trans) was not confirmed (Muramatsu H et al. Genet. Med., 2017 07;19:796-802). This alteration has also been reported in individuals with ovarian, breast and aggressive prostate cancer (Jakubowska A et al. Eur J Hum Genet. 2003 Dec;11(12):955-8; Eccles DM et al. Ann. Oncol., 2016 Mar;27:467-73; Song H et al. Hum. Mol. Genet., 2014 Sep;23:4703-9; Rebbeck TR et al. Breast Cancer Res., 2016 11;18:112; Pritchard CC et al. N. Engl. J. Med., 2016 Aug;375:443-53). This alteration has been classified as pathogenic by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, and mutation co-occurrence (Parsons MT et al. Hum. Mutat. 2019 09;40(9):1557-1578). Of note, this alteration is also designated as IVS6-2A>G in published literature. This nucleotide position is well 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 and functional studies from both patient derived material and minigene assay show that this alteration causes skipping of coding exon 6 (Ambry internal data; Houdayer C et al. Hum Mut. 2012; 33:1228–38; Fraile-Bethencourt E et al. J. Pathol. 2019 08;248(4):409-420). Based on the majority of available evidence to date, this variant is likely to be pathogenic. However, because this variant is identified in one or more patients with Fanconi Anemia it may be hypomorphic and thus, carriers of this variant and their families may present with reduced risks, and not with the typical clinical characteristics of a high-risk pathogenic BRCA2 alteration. As risk estimates are unknown at this time, clinical correlation is advised.
GeneDx RCV000221055 SCV000279588 pathogenic not provided 2017-12-13 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.517-2A>G or IVS6-2A>G and consists of a A>G nucleotide substitution at the -2 position of intron 6 of the BRCA2 gene. Using alternate nomenclature, this variant would be defined as BRCA2 745-2A>G. This variant destroys a canonical splice acceptor site and is predicted to cause abnormal gene splicing, leading to either an abnormal message that is subject to nonsense-mediated mRNA decay or to an abnormal protein product. Consistent with splicing predictions, Houdayer et al. (2012) studied this variant in a PAXgene assay and observed complete skipping of exon 7. Furthermore, this variant has been observed in individuals diagnosed with ovarian, early-onset breast, or aggressive prostate cancer (Jakubowska 2003, Song 2014, Eccles 2016, Plaskocinska 2016, Pritchard 2016). Based on currently available evidence, we consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077347 SCV000327158 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000044589 SCV000591692 pathogenic Hereditary breast and ovarian cancer syndrome criteria provided, single submitter clinical testing
Department of Medical Genetics, Oslo University Hospital RCV000077347 SCV000605706 pathogenic Breast-ovarian cancer, familial 2 2017-01-20 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000044589 SCV000605808 pathogenic Hereditary breast and ovarian cancer syndrome 2016-12-23 criteria provided, single submitter clinical testing The c.517-2A>G variant in BRCA2 has been reported in at least 6 individuals with BRCA2-associated cancers (Jakubowska 2003, Breast Cancer Information Core (BIC) database) and was absent from large population studies. In vitro functional stu dies provide some evidence that the c.517-2A>G variant may impact protein functi on (Houdayer 2012). This variant occurs in the invariant region (+/- 1,2) of the splice consensus sequence and is predicted to cause altered splicing leading to an abnormal or absent protein. Heterozygous loss of function of the BRCA2 gene is an established disease mechanism in hereditary breast and ovarian cancer (HBO C). In summary, this variant meets criteria to be classified as pathogenic for H BOC in an autosomal dominant manner.
Counsyl RCV000077347 SCV000677664 pathogenic Breast-ovarian cancer, familial 2 2017-05-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044589 SCV000694836 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.517-2A>G is located in a canonical splice-site and is predicted to affect mRNA splicing resulting in a significantly altered protein due to either exon skipping, shortening, or inclusion of intronic material. Several computational tools predict a significant impact on normal splicing: Five predict the variant abolishes a 3 acceptor site. Experimental evidence are in support of these predictions and demonstrated exon 7 skipping following in vitro analysis (Houdayer_2012). The variant was absent in 251306 control chromosomes (gnomAD). c.517-2A>G has been reported in the literature in multiple individuals affected with Hereditary Breast and Ovarian Cancer and also prostate cancer (e.g. Jakubowska_2003, Pritchard_2016, Rebbeck_2018, Song_2014, Walsh_2011). These data indicate that the variant is very likely to be associated with disease. Nine ClinVar submitters (evaluation after 2014) cite the variant as pathogenic/likely pathogenic. Based on the evidence outlined above, the variant was classified as pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000221055 SCV000887844 pathogenic not provided 2017-12-27 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162897 SCV000904690 pathogenic Hereditary cancer-predisposing syndrome 2020-12-21 criteria provided, single submitter clinical testing This variant causes an A to G nucleotide substitution at the -2 position of intron 6 of the BRCA2 gene. Functional RNA studies have shown that this variant causes exon 7 skipping, resulting in premature truncation (PMID: 22505045, 30883759, 31843900). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast or ovarian cancer (PMID: 14647210, 22006311, 22505045, 24240112, 24728189, 26681682) or prostate cancer (PMID: 27433846). 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) RCV000077347 SCV000109144 likely pathogenic Breast-ovarian cancer, familial 2 2011-01-06 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077347 SCV000147050 pathogenic Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000044589 SCV000587554 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
King Laboratory,University of Washington RCV001171442 SCV001251353 pathogenic Breast-ovarian cancer, familial 2; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research

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