ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8243G>A (p.Gly2748Asp) (rs80359071)

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Total submissions: 15
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000216216 SCV000274383 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-26 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s),Other strong data supporting pathogenic classification
Breast Cancer Information Core (BIC) (BRCA2) RCV000113895 SCV000147307 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Color RCV000216216 SCV000689109 pathogenic Hereditary cancer-predisposing syndrome 2017-08-01 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000113895 SCV000327843 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000113895 SCV000677699 pathogenic Breast-ovarian cancer, familial 2 2016-11-28 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000045460 SCV000592180 likely pathogenic Hereditary breast and ovarian cancer syndrome 2012-09-26 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113895 SCV000244484 pathogenic Breast-ovarian cancer, familial 2 2015-08-10 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 = 1
GeneDx RCV000481847 SCV000568124 pathogenic not provided 2018-09-14 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.8243G>A at the cDNA level, p.Gly2748Asp (G2748D) at the protein level, and results in the change of a Glycine to an Aspartic Acid (GGT>GAT). Using alternate nomenclature, this variant has been previously published as BRCA2 8471G>A. This variant has been observed in multiple families with Hereditary Breast and Ovarian Cancer (Claes 2004, Easton 2007, Farrugia 2008, Lee 2014, Lin 2016). The variant was strongly predicted by Easton et al. (2007) and Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence with pathogenic variants. Homologous recombination assays, centrosome amplification analysis, and complementation studies are consistent with BRCA2 Gly2748Asp having a pathogenic effect (Farrugia 2008, Balia 2011, Guidugli 2013, Spugnesi 2013, Hendriks 2014). BRCA2 Gly2748Asp was not observed at a significant allele frequency in large population cohorts (Lek 2016). Since Glycine and Aspartic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Gly2748Asp is located within a DSS1 contacting residue of the DNA binding domain (Yang 2002). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, we consider this variant to be pathogenic.
Human Genome Sequencing Center Clinical Lab,Baylor College of Medicine RCV000113895 SCV000839922 pathogenic Breast-ovarian cancer, familial 2 2018-03-05 criteria provided, single submitter clinical testing This c.8243G>A (p.Gly2748Asp) variant in the BRCA2 gene has been reported in multiple breast cancer and ovarian cancer patients [PMID 15026808, 22711857] while only observed with extremely low allele frequency in general population according to gnomad database. Glycine at amino acid position 2748 is highly conserved during evolution. Functional studies showed that this mutant causes reduced homology-directed recombination repair activity, compared to wild type [PMID:18451181, 23328489, 25146914]. Multiple in silico predictions suggest this glycine to asparatic acid change is deleterious. Based upon above evidences, this c.8243G>A (p.Gly2748Asp) variant in the BRCA2 gene is classified as pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000045460 SCV000695136 likely pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-04 criteria provided, single submitter clinical testing Variant Summary: The variant c.8243G>A causes a missense change from Gly to Asp involving a conserved nucleotide with 5/5 in silico tools predicting a "deleterious" outcome. The variant of interest was not observed in controls (ExAC, 1000 Gs or ESP) and has been reported in several HBOC patients/families via publications and in individuals undergoing BRCA1/2 testing by clinical labs. However, no cosegregation studies for the variant have been reported so far in literature. Multiple independent functional studies demonstrated a deleterious impact by the variant resulting in impaired homologous recombination activity of BRCA2 further supporting a disease-causing impact (Hendriks_2014, Guidugli_2012, and Farrugia_2009). Furthermore, multiple reputable databases/clinical laboratories report the variant as "Causal/Pathogenic." Multifactorial probability models are also consistent with the disease-causing outcome of the variant (Easton_2007, Farrugia_2008, Karchin_2008, and Lindor_2012). Taking all available lines of evidence into consideration, the variant of interest is classified as likely pathogenic until additional information (such as the variants cosegregation with disease) becomes available.
Invitae RCV000045460 SCV000073473 pathogenic Hereditary breast and ovarian cancer syndrome 2018-11-21 criteria provided, single submitter clinical testing This sequence change replaces glycine with aspartic acid at codon 2748 of the BRCA2 protein (p.Gly2748Asp). The glycine residue is highly conserved and there is a moderate physicochemical difference between glycine and aspartic acid. This variant is not present in population databases (rs80359071, ExAC no frequency). This variant has been reported in individuals affected with breast and/or ovarian cancer (PMID: 15026808, 17924331, 22711857). ClinVar contains an entry for this variant (Variation ID: 52535). Based on a multifactorial likelihood algorithm using genetic data, this variant has been determined to have a high probability of being pathogenic (PMID: 17924331). Experimental studies have shown that this missense change disrupts homology directed recombination and the regulation of centrosome amplification (PMID: 18451181, 21671020, 23108138, 23328489, 25146914). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000045460 SCV000605806 pathogenic Hereditary breast and ovarian cancer syndrome 2016-12-21 criteria provided, single submitter clinical testing The p.Gly2748Asp variant in BRCA2 has been reported in at least 10 individuals w ith BRCA2-associated cancers (Claes 2014, Breast Cancer Information Core (BIC) d atabase), and it was absent from large population studies. In vitro functional s tudies provide some evidence that the p.Gly2748Asp variant may impact protein fu nction (Guidugli 2014, Spugnesi 2013). In addition, this variant was classified as Pathogenic on August 10, 2015 by the ClinGen-approved ENIGMA expert panel (Cl inVar SCV000244484.1). In summary, this variant meets criteria to be classified as pathogenic for HBOC in an autosomal dominant manner.
Mendelics RCV000045460 SCV000838871 pathogenic Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000481847 SCV000296703 pathogenic not provided 2015-03-30 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000113895 SCV000297564 pathogenic Breast-ovarian cancer, familial 2 2010-04-26 no assertion criteria provided clinical testing

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