ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7988A>T (p.Glu2663Val) (rs80359031)

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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 RCV000163034 SCV000213522 pathogenic Hereditary cancer-predisposing syndrome 2017-01-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other strong data supporting pathogenic classification,Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Breast Cancer Information Core (BIC) (BRCA2) RCV000077422 SCV000147242 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735605 SCV000324885 pathogenic Breast and/or ovarian cancer 2016-01-28 criteria provided, single submitter clinical testing
Color RCV000163034 SCV000911875 pathogenic Hereditary cancer-predisposing syndrome 2017-12-13 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077422 SCV000327790 pathogenic Breast-ovarian cancer, familial 2 2015-10-02 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000257984 SCV000592166 pathogenic Hereditary breast and ovarian cancer syndrome 2013-05-16 criteria provided, single submitter clinical testing
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000077422 SCV000244478 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
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735605 SCV000863743 pathogenic Breast and/or ovarian cancer 2011-02-14 no assertion criteria provided clinical testing
Fulgent Genetics,Fulgent Genetics RCV000763327 SCV000894004 pathogenic Familial cancer of breast; Breast-ovarian cancer, familial 2; Fanconi anemia, complementation group D1; Medulloblastoma; Wilms tumor 1; Malignant tumor of prostate; Pancreatic cancer 2; Glioma susceptibility 3 2018-10-31 criteria provided, single submitter clinical testing
GeneDx RCV000484277 SCV000564796 pathogenic not provided 2018-06-26 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.7988A>T at the cDNA level, p.Glu2663Val (E2663V) at the protein level, and results in the change of a Glutamic Acid to a Valine (GAA>GTA). Also defined as BRCA2 8216A>T using alternate nomenclature, this variant has been reported in several individuals with breast and/or ovarian cancer (Chenevix-Trench 2006, Borg 2010, Akbari 2011, Couch 2015). While this variant has been shown to induce aberrant splicing resulting in various alternate transcripts, it has also been demonstrated to reduce homologous repair activity and increase centrosome amplification when present in the full-length protein (Farrugia 2008, Sanz 2010, Walker 2010, Fraile-Bethencourt 2017). In addition, this variant was unable to rescue cell viability in BRCA2-deficient cells (Kuznetsov 2008). Furthermore, this mutation was strongly predicted by Lindor et al. (2012) to be pathogenic based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants. BRCA2 Glu2663Val was not observed in large population cohorts (Lek 2016). This variant is located within the DNA binding domain (Yang 2002). In silico analyses, which include protein and splice predictors as well as evolutionary conservation, are inconsistent in their assessment as to whether or not the variant is damaging. Based on currently available evidence, we consider BRCA2 Glu2663Val to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000257984 SCV000695117 pathogenic Hereditary breast and ovarian cancer syndrome 2017-05-01 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7988A>T (p.Glu32663Val) variant causes a missense change involving the alteration of a highly conserved nucleotide. The variant is located within located within the DNA binding domain and 5/5 in silico tools predict a damaging outcome for this variant. 5/5 programs in Alamut predict that this variant disrupts an ESE. A combination of quantitative isoform-specific real-time PCR, cDNA sequencing, and quantitative allele-specific PCR showed that the variant is associated with abnormal splicing, however, the levels of full-length isoform encoding wildtype/E2663V was 80-90% and only 10% lead to a truncated transcript (Farrugia, 2008; Fraile-Bethencourt, 2017). These data suggest that deleterious effect of the variant could be due to other molecular mechanisms. The Glu2663Val was to proven to abrogate variant protein function by experimental studies demonstrating a disruption of BRCA2 homology-directed repair activity, increased centrosome amplification, and inability to rescue the lethality of BRCA2-deficient ES-cells (Kuznetsov, 2008; Walker, 2010). The c.7988A>T was not identified in large, broad control datasets of ExAC and gnomAD (~118364 and ~245100 chrs tested, respectively), but has been reported in multiple HBOC individuals and, reportedly, segregated with the disease in several families (Kuznetsov, 2008). Lastly, multiple clinical diagnostic laboratories/reputable databases classified this variant as Likely Pathogenic/Pathogenic. Taken together, based on all available evidence and further supported by the ACMG guidelines, this variant is classified as Pathogenic.
Invitae RCV000257984 SCV000073388 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-03 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with valine at codon 2663 of the BRCA2 protein (p.Glu2663Val). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and valine. This variant is not present in population databases (ExAC no frequency). This variant has been identified in individuals with a personal and/or family history of breast/ovarian cancer (PMID: 16489001, 20104584, 21965345, 25452441). This variant is also known as 8216A>T in the literature. ClinVar contains an entry for this variant (Variation ID: 52462). Experimental studies have shown that this variant disrupts BRCA2 homology-directed repair activity, leads to centrosome amplification, and is not able to rescue the lethality of BRCA2-deficient ES-cells (PMID: 18607349, 20513136). This missense change has also been shown to increase the naturally occurring skipping of exon 18 that is expected to result in an absent or disrupted protein product (PMID: 20215541, 20513136, 23893897, 28339459). Based on multifactorial likelihood algorithms using genetic, in silico, functional and statistical data, this variant has been determined to have a high probability of being deleterious (PMID: 17924331, 18451181, 21990134). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000257984 SCV000966918 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-03-09 criteria provided, single submitter clinical testing The p.Glu2663Val variant in BRCA2 has been reported in at least 9 individuals wi th BRCA2-associated cancers (Breast Cancer Information Core database: https://re search.nhgri.nih.gov/projects/bic/, Szabo 2000, Chevenix-Trench 2006, Borg 2010, Akbari 2011), and was absent from large population studies. In vitro functional studies suggest that this variant may alter protein function (Kuznetsov 2008, F arrugia 2008, Sanz 2010, Walker 2010, Whiley 2014, Fraile-Bethencourt 2017). Com putational prediction tools and conservation analysis also suggest that the p.Gl u2663Val variant may impact the protein. In addition, this variant was classifie d as pathogenic on August 10, 2015 by the ClinGen-approved ENIGMA expert panel ( ClinVar SCV000244478.1). In summary, although additional studies are required to fully establish its clinical significance, the p.Glu2663Val variant is likely p athogenic. ACMG/AMP Criteria applied (Richards 2015): PM2, PS3_Supporting, PS4_M oderate, PP3.
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000257984 SCV000587928 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Sharing Clinical Reports Project (SCRP) RCV000077422 SCV000109220 pathogenic Breast-ovarian cancer, familial 2 2012-02-24 no assertion criteria provided clinical testing

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