ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.7988A>T (p.Glu2663Val) (rs80359031)

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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) 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
Invitae RCV000257984 SCV000073388 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-17 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.
Ambry Genetics RCV000163034 SCV000213522 pathogenic Hereditary cancer-predisposing syndrome 2019-02-14 criteria provided, single submitter clinical testing The p.E2663V pathogenic mutation (also known as c.7988A>T), located in coding exon 17 of the BRCA2 gene, results from an A to T substitution at nucleotide position 7988. The glutamic acid at codon 2663 is replaced by valine, an amino acid with dissimilar properties. This alteration was identified 18 families in a worldwide study of BRCA1/2 mutation positive families (Rebbeck TR et al. Hum. Mutat.. 2018 05;39:593-620). In one study, RT-PCR analysis demonstrated that this alteration leads to an out-of-frame deletion of the 355-bp exon 18, resulting in a premature stop codon within exon 19 (Farrugia DJ et al. Cancer Res. 2008 May; 68(9):3523-31). Functional studies from other research groups have confirmed these findings; however, in addition to the transcript that skips only exon 18, they found that this alteration also leads to the transcription of an isoform that skips both exon 17 and 18 as well as a full-length variant transcript (Walker LC et al. Hum. Mutat. 2010 Jun; 31(6):E1484-505; Fraile-Bethencourt E et al. PLoS Genet. 2017 Mar;13:e1006691). Further studies assessed the function of the variant protein and demonstrated abrogated function consistent with pathogenicity; homolgous repair activity was reduced significantly compared to wildtype BRCA2. This alteration has been classified as pathogenic (p>0.99) 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, mutation co-occurrence, and functional assay results (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8). It has also been classified as likely deleterious based on a protein likelihood ratio (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16). Of note, this alteration is also referred to as 8216A>T in some published literature. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
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
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
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.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp 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.
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
Color Health, Inc RCV000163034 SCV000911875 pathogenic Hereditary cancer-predisposing syndrome 2021-01-11 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with valine at codon 2663 of the BRCA2 protein. Computational prediction is inconclusive regarding the impact of this variant on protein structure and function (internally defined REVEL score threshold 0.5 < inconclusive < 0.7, PMID: 27666373). Functional RNA studies have shown that this variant causes exon 18 skipping or partial exon 18 deletion, resulting in frameshift truncation in either case (PMID: 18451181, 20215541, 20513136). To our knowledge, functional studies have not been reported for this variant. This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 18446624, 18451181, 20104584, 21965345, 25452441). 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 ( Based on the available evidence, this variant is 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, 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.
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001001328 SCV001158515 pathogenic not specified 2019-05-23 criteria provided, single submitter clinical testing The BRCA2 c.7988A>T; p.Glu2663Val variant (rs80359031), also known as 8216A>T, is reported in the literature in multiple individuals affected with breast and ovarian cancer (Akbari 2011, Borg 2010, Chenevix-Trench 2006, Couch 2015). Functional analyses demonstrate aberrant splicing, reduced protein function, and a failure to rescue a mouse knockout cell line (Farrugia 2008, Fraile-Bethencourt 2017, Kuznetsov 2008, Sanz 2010, Walker 2010). This variant is reported as pathogenic by multiple laboratories in ClinVar (Variation ID: 52462), and is absent from general population databases (Exome Variant Server, Genome Aggregation Database), indicating it is not a common polymorphism. The glutamic acid at codon 2663 is highly conserved, and computational analyses (SIFT, PolyPhen-2) predict that this variant is deleterious. Based on available information, this variant is considered to be pathogenic. References: Akbari MR et al. Clinical impact of unclassified variants of the BRCA1 and BRCA2 genes. J Med Genet. 2011 Nov;48(11):783-6. Borg A et al. Characterization of BRCA1 and BRCA2 deleterious mutations and variants of unknown clinical significance in unilateral and bilateral breast cancer: the WECARE study. Hum Mutat. 2010 Mar;31(3):E1200-40. Chenevix-Trench G et al. Genetic and histopathologic evaluation of BRCA1 and BRCA2 DNA sequence variants of unknown clinical significance. Cancer Res. 2006 Feb 15;66(4):2019-27. Couch FJ et al. Inherited mutations in 17 breast cancer susceptibility genes among a large triple-negative breast cancer cohort unselected for family history of breast cancer. J Clin Oncol. 2015 Feb 1;33(4):304-11. Farrugia DJ et al. Functional assays for classification of BRCA2 variants of uncertain significance. Cancer Res. 2008 May 1;68(9):3523-31. Fraile-Bethencourt E et al. Functional classification of DNA variants by hybrid minigenes: Identification of 30 spliceogenic variants of BRCA2 exons 17 and 18. PLoS Genet. 2017 Mar 24;13(3):e1006691. Kuznetsov SG et al. Mouse embryonic stem cell-based functional assay to evaluate mutations in BRCA2. Nat Med. 2008 Aug;14(8):875-81. Sanz DJ et al. A high proportion of DNA variants of BRCA1 and BRCA2 is associated with aberrant splicing in breast/ovarian cancer patients. Clin Cancer Res. 2010 Mar 15;16(6):1957-67. Walker LC et al. Detection of splicing aberrations caused by BRCA1 and BRCA2 sequence variants encoding missense substitutions: implications for prediction of pathogenicity. Hum Mutat. 2010 Jun;31(6):E1484-505.
Sharing Clinical Reports Project (SCRP) RCV000077422 SCV000109220 pathogenic Breast-ovarian cancer, familial 2 2012-02-24 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077422 SCV000147242 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 RCV000257984 SCV000587928 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000077422 SCV000592166 pathogenic Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing The BRCA2 p.Glu2663Val variant has been identified in 4/5646 proband chromosomes (frequency 0.001) of individuals with breast and/or ovarian cancer, and was not identified in 360 control chromosomes, increasing the likelihood this variant may have clinical significance (Akbari_2011_21965345, Borg_2010_20104584, Chenevix-Trench_2006_16489001, Sanz_2010_20215541, Walker_2010_20513136). The variant is listed in the dbSNP database (ID: rs80359031), but no frequency information was provided, and so the prevalence of this variant in the general population is not known. It has been reported in the BIC (9x) database as a variant of unknown significance. The p.Glu2663 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Glu2663Val variant may impact the protein. Additionally, computational prediction software (SpliceSiteFinder, MaxEntScan, NNSPLICE, HumanSpliceFinder) predicts this variant could potentially generate a cryptic splice site; however, these in silico tools are not predictive enough to assume pathogenicity. Functional studies evaluating splicing predict this variant to be deleterious (Capanu_2011_21520273, Farrugia_2008_18451181, Karachin_2008_19043619, Kuznetsov_2008_16489001, Lindor_2012_21990134); Farrugia et al 2008 demonstrated this variant results in skiipping of exon 18 and is predicted to cause a premature truncation of the BRCA2 protein. However, one study evaluating LOH in tumours identified this variant on the lost allele suggesting neutrality (Chenevix-Trench_2006_16489001). Cosegregation analysis based on data compiled by Myriad Genetics calculated this variant to have odds of 233:1 in favour of causality (Easton_2007_17924331). The variant has been shown to segregate with cancer in multiple families in Myriad's internal data (personal communication). In summary, based on the above information, this variant is classified as pathogenic.
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

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