ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7976G>A (p.Arg2659Lys) (rs80359027)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045366 SCV000073379 pathogenic Hereditary breast and ovarian cancer syndrome 2020-10-23 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 observed 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.
Ambry Genetics RCV000131687 SCV000186723 pathogenic Hereditary cancer-predisposing syndrome 2019-02-07 criteria provided, single submitter clinical testing The c.7976G>A pathogenic mutation (also known as p.R2659K), located in coding exon 16 of the BRCA2 gene, results from a G to A substitution at nucleotide position 7976. This change occurs in the last base pair of coding exon 16, which makes it likely to have some effect on normal mRNA splicing. In addition to potential splicing impact, this alteration changes the arginine at codon 2659 to lysine, an amino acid with highly similar properties. Multiple studies have demonstrated that this alteration leads to the skipping of coding exon 16, resulting in an in-frame deletion of 57 amino acids (Ambry internal data; Hofmann W et al. J. Med. Genet. 2003 Mar;40:e23; Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13(3):e1006691). In addition to the splicing impact, functional studies have demonstrated that this alteration, which is located in the COOH-terminal DNA binding domain, inactivates BRCA2 protein function (Wu K et al. Cancer Res. 2005 Jan;65:417-26). This alteration has been detected in numerous breast and/or ovarian cancer families (Rebbeck TR et al. Hum. Mutat. 2018 May;39(5):593-620). Based on the available evidence, this alteration is interpreted as a disease-causing mutation.
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.
Color Health, Inc RCV000131687 SCV000292161 pathogenic Hereditary cancer-predisposing syndrome 2015-03-06 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000212266 SCV000296757 pathogenic not provided 2019-05-28 criteria provided, single submitter clinical testing Statistically enriched in patients compared to ethnically matched controls. Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function.
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
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
GeneKor MSA RCV000045366 SCV000693583 pathogenic Hereditary breast and ovarian cancer syndrome 2020-01-01 criteria provided, single submitter clinical testing This variant is a single base substitution at the last nucleotide of exon 17 of the BRCA2 coding sequence which results in a single amino acid change from Arginine to Lysine at amino acid residue 2659 of the BRCA2 gene. The Arginine residue is highly conserved in a functional domain of the protein and there is a small physiochemical difference between Arginine and Lysine (Grantham Score 26). This variant has been reported in the literature in patients with breast and/or ovarian cancer (PMID: 12624152, 24010542, 26681312). This variant is also known as 8204G>A in the international literature and is present in population databases at a low frequency (rs80359027, <0.01%). Nucleotide substitutions within the consensus splice site are relatively common causes of aberrant splicing (PMID: 17576681). RNA analyses of patients carrying this variant 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 variant showed that results in inactivation of the BRCA2 protein and a cytoplasmic localization (PMID: 15695382). The mutation database ClinVar contains an entry for this variant (Variation ID: 38131).
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
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
Clinical Genetics Karolinska University Hospital,Karolinska University Hospital RCV000212266 SCV001449881 pathogenic not provided 2017-01-25 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031713 SCV000054320 pathogenic Breast-ovarian cancer, familial 2 2012-09-21 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031713 SCV000147235 uncertain significance 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 RCV000045366 SCV000587923 pathogenic Hereditary breast and ovarian cancer syndrome 2015-12-17 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000031713 SCV000733310 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
German Consortium for Hereditary Breast and Ovarian Cancer Center Cologne,University Hospital Cologne RCV000785230 SCV000923798 pathogenic Neoplasm of ovary 2018-12-01 no assertion criteria provided research
King Laboratory,University of Washington RCV001171449 SCV001251360 pathogenic Breast-ovarian cancer, familial 2; Hereditary breast and ovarian cancer syndrome 2019-09-01 no assertion criteria provided research
GenomeConnect, ClinGen RCV000031713 SCV001423284 not provided Breast-ovarian cancer, familial 2 no assertion provided phenotyping only Variant interpretted as Pathogenic and reported on 12-11-2017 by Lab or GTR ID 26957. GenomeConnect assertions are reported exactly as they appear on the patient-provided report from the testing laboratory. GenomeConnect staff make no attempt to reinterpret the clinical significance of the variant.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001358381 SCV001554097 pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Arg2659Lys variant was identified in 4 of 6566 proband chromosomes (frequency: 0.0006) from individuals or families with pancreatic, prostate, breast or ovarian cancer (Johns 2017, Konstantopoulou 2014, Pritzlaff 2016, Tung 2015). The variant was also identified in dbSNP (ID: rs80359027 as "With Pathogenic allele"), ClinVar (classified as pathogenic by Invitae, Ambry Genetics, GeneDx and eleven other submitters), and LOVD 3.0 (28x as pathogenic). The variant was not identified in UMD-LSDB. The variant was identified in control databases in 1 of 245888 chromosomes at a frequency of 0.000004 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the European population in 1 of 111412 chromosomes (freq: 0.000009), but not in the African, Other, Latino, Ashkenazi Jewish, East Asian, Finnish, or South Asian populations. RT-PCR analysis of the variant showed an in-frame deletion of 171 bp, resulting in a deletion of 57 amino acids (Hofman 2003, Farrugia 2008). In addition, one study showed that this variant abolished the interaction between the oligosaccharide binding folds of BRCA2 and PAR (Poly ADP-ribose; Zhang 2015). The p.Arg2659 residue is conserved across mammals and other organisms, and four out of five computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The p.Arg2659Lys variant occurs in the last three bases of the exon. This position has been shown to be part of the splicing consensus sequence and variants involving this position sometimes affect splicing. In addition, 2 of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) predict a greater than 10% difference in splicing. In summary, based on the above information, this variant meets our laboratory’s criteria to be classified as pathogenic.

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