ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7976G>A (p.Arg2659Lys) (rs80359027)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131687 SCV000186723 pathogenic Hereditary cancer-predisposing syndrome 2018-01-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),Functionally-validated splicing mutation,Other strong data supporting pathogenic classification,Last nucleotide of exon
Breast Cancer Information Core (BIC) (BRCA2) RCV000031713 SCV000147235 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000045366 SCV000586979 pathogenic Hereditary breast and ovarian cancer syndrome 2017-04-18 criteria provided, single submitter clinical testing
Color RCV000131687 SCV000292161 pathogenic Hereditary cancer-predisposing syndrome 2015-03-06 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031713 SCV000327779 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000031713 SCV000488467 pathogenic Breast-ovarian cancer, familial 2 2016-04-07 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031713 SCV000744528 pathogenic Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031713 SCV000733310 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
GeneDx RCV000212266 SCV000210454 pathogenic not provided 2018-09-19 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.7976G>A at the cDNA level. Located in the last nucleotide of exon 17, it destroys a natural splice donor site and causes abnormal splicing. RNA and minigene analyses have demonstrated that this variant, also known as BRCA2 8204G>A using alternate nomenclature, causes complete skipping of exon 17 and results in an in-frame deletion of 171 bases (Hoffman 2003, Fraile-Bethencourt 2017). This in-frame deletion has been shown to result in inactivation of BRCA2 function with respect to cellular localization, cell survival, homologous recombination repair, and centrosome regulatory functions (Hoffman 2003, Wu 2005, Farrugia 2008, Zhang 2015). Furthermore, multifactorial models have strongly predicted this variant to be pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence data (Easton 2007, Lindor 2012). This variant has been observed in individuals with a personal and/or family history of breast cancer, as well as in at least one individual with a non-small cell neuroendocrine carcinoma of the ovary (Konstantopoulou 2014, Susswein 2015, Pritzlaff 2017, Herold 2018). Although the nucleotide substitution results in the change of an Arginine to a Lysine at codon 2659, and is called Arg2659Lys (R2569K) in the literature, we are using only the nucleotide nomenclature to refer to the variant since the defect is determined to be one of splicing rather than a resulting missense variant. BRCA2 c.7976G>A was not observed at a significant allele frequency in large population cohorts (Lek 2016). The nucleotide which is altered, a guanine (G) at base 7976, is conserved across species. Based on the current evidence, we consider this variant to be pathogenic.
GeneKor MSA RCV000045366 SCV000693583 pathogenic Hereditary breast and ovarian cancer syndrome 2017-11-01 criteria provided, single submitter clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785230 SCV000923798 pathogenic Ovarian Neoplasms 2018-12-01 no assertion criteria provided research
Integrated Genetics/Laboratory Corporation of America RCV000045366 SCV000695112 pathogenic Hereditary breast and ovarian cancer syndrome 2016-08-08 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7976G>A (p.Arg2659Lys) variant involves the alteration of a conserved nucleotide located at the end of exon17. 4/5 in silico tools predict a damaging outcome for this variant. One of five splice prediction tools predicts significant impact on normal splicing. Functional studies show that this variant leads to skipping of exon 17, which results in-frame deletion of 57 highly conserved amino acids which constitute a part of OB and helical domains (InterPro). This in-frame deletion has been shown to result in inactivation cellular localization, cell survival, homologous recombination repair, and centrosome regulatory functions. This variant was found in 1/122178 control chromosomes at a frequency of 0.0000082, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). It has been widely reported as a pathogenic variant in literature and clinical databases found in several HBOC patients/families. Multifactorial probability models also strongly suggest for pathogenicity. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as Pathogenic.
Invitae RCV000045366 SCV000073379 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-04 criteria provided, single submitter clinical testing This sequence change replaces arginine with lysine at codon 2659 of the BRCA2 protein (p.Arg2659Lys). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and lysine. It also falls at the last nucleotide of exon 17 of the BRCA2 coding sequence. This variant is present in population databases (rs80359027, ExAC 0.002%). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 12624152, 24010542, 26681312, 25186627). It is also known as 8204G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 38131). Nucleotide substitutions at the last nucleotide of the exon are relatively common causes of aberrant splicing (PMID: 17576681). Analysis of patient lymphocyte mRNA (PMID: 12624152) and results of a minigene assay (PMID: 28339459) have shown that this variant causes aberrant splicing, resulting in skipping of exon 17 and a loss of 57 amino acid residues from the BRCA2 protein. Experimental analysis of the functional effects of this splicing defect showed that it results in an inactive BRCA2 protein localized in the cytoplasm (PMID: 15695382). Based on multifactorial likelihood analyses using genetic evidence from a large database of tested individuals, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331, 21990134, 18451181). For these reasons, this variant has been classified as Pathogenic.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212266 SCV000296757 pathogenic not provided 2014-12-18 criteria provided, single submitter clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000045366 SCV000587923 pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000031713 SCV000054320 pathogenic Breast-ovarian cancer, familial 2 2012-09-21 no assertion criteria provided clinical testing

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