ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9004G>A (p.Glu3002Lys) (rs80359152)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000045685 SCV000883481 pathogenic not provided 2017-05-10 criteria provided, single submitter clinical testing The BRCA2 c.9004G>A; p.Glu3002Lys variant (rs80359152) has been reported in several individuals and families with breast and/or ovarian cancer (Belanger 2015, Cavallone 2010, Cote 2012, Palmero 2016, Salazar 2006). Functional studies show that this variant is unable to rescue BRCA2 null embryonic stem cells, has reduced homology-directed repair activity, and affects cytokinesis (Biswas 2012, Guidugli 2013, Mondal 2012). This variant is listed in ClinVar (Variation ID: 38201), and is absent from the general population databases (1000 Genomes Project, Exome Variant Server, Genome Aggregation Database). The glutamate at codon 3002 is a highly conserved residue in the DNA-binding domain, and computational algorithms (SIFT, PolyPhen2, MutationTaster, Align GVGD, Prior Probabilities) predict this variant to be damaging to the protein. Taken together, this variant is considered pathogenic. REFERENCES Link to ClinVar database for p.Glu3002Lys: https://www.ncbi.nlm.nih.gov/clinvar/variation/38201/ Belanger MH et al. A targeted analysis identifies a high frequency of BRCA1 and BRCA2 mutation carriers in women with ovarian cancer from a founder population. J Ovarian Res. 2015 Mar 27;8:1. Biswas K et al. Functional evaluation of BRCA2 variants mapping to the PALB2-binding and C-terminal DNA-binding domains using a mouse ES cell-based assay. Hum Mol Genet. 2012 Sep 15;21(18):3993-4006. Cavallone L et al. Comprehensive BRCA1 and BRCA2 mutation analyses and review of French Canadian families with at least three cases of breast cancer. Fam Cancer. 2010 Dec;9(4):507-17. Cote S et al. The BRCA2 c.9004G>A (E2002K) [corrected] variant is likely pathogenic and recurs in breast and/or ovarian cancer families of French Canadian descent. Breast Cancer Res Treat. 2012 Jan;131(1):333-40. Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75. Mondal G et al. BRCA2 localization to the midbody by filamin A regulates cep55 signaling and completion of cytokinesis. Dev Cell. 2012 Jul 17;23(1):137-52. Palmero EI et al. Screening for germline BRCA1, BRCA2, TP53 and CHEK2 mutations in families at-risk for hereditary breast cancer identified in a population-based study from Southern Brazil. Genet Mol Biol. 2016 May 24;39(2):210-22. Salazar R et al. BRCA1-2 mutations in breast cancer: identification of nine new variants of BRCA1-2 genes in a population from central Western Spain. Cancer Lett. 2006 Feb 20;233(1):172-7.
Ambry Genetics RCV000130642 SCV000185521 likely pathogenic Hereditary cancer-predisposing syndrome 2017-12-12 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Deficient protein function in appropriate functional assay(s),In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting pathogenic classification,Rarity in general population databases (dbsnp, esp, 1000 genomes),Moderate segregation with disease (at least 3 informative meioses) for rare diseases.
Breast Cancer Information Core (BIC) (BRCA2) RCV000031784 SCV000147510 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735616 SCV000902216 pathogenic Breast and/or ovarian cancer 2017-03-07 criteria provided, single submitter clinical testing
Color RCV000130642 SCV000684014 pathogenic Hereditary cancer-predisposing syndrome 2016-11-10 criteria provided, single submitter clinical testing
Counsyl RCV000031784 SCV000488701 likely pathogenic Breast-ovarian cancer, familial 2 2016-06-01 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000195385 SCV000592246 likely pathogenic Hereditary breast and ovarian cancer syndrome 2012-11-08 criteria provided, single submitter clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735616 SCV000863754 pathogenic Breast and/or ovarian cancer 2012-03-06 no assertion criteria provided clinical testing
GeneDx RCV000045685 SCV000210490 pathogenic not provided 2018-08-22 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA2 c.9004G>A at the cDNA level, p.Glu3002Lys (E3002K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant, also known as BRCA2 9232G>A using alternate nomenclature, has been observed in multiple individuals with familial and early-onset breast and/or ovarian cancer and was shown to segregate with disease in several families (Cavallone 2010, Cote 2012, Biswas 2012, Belanger 2015). It is noted as a recurrent variant in individuals of French-Canadian descent (Cote 2012, Belanger 2015, Gostimir 2016). Although in silico analysis predicts that this variant does not alter protein structure/function, published functional studies showed this variant resulted in decreased homology-directed repair activity and lacked ability to rescue cell growth (Biswas 2012, Guidugli 2013). BRCA2 Glu3002Lys was not observed in large population cohorts (Lek 2016). BRCA2 Glu3002Lys is located in the DNA binding domain (Yang 2002). Based on currently available evidence, we consider this variant to be pathogenic.
Integrated Genetics/Laboratory Corporation of America RCV000195385 SCV000695199 pathogenic Hereditary breast and ovarian cancer syndrome 2016-04-20 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9004G>A variant affects a conserved nucleotide, resulting in amino acid change from a negatively charged Glu to a positively charged Lys. 4/5 in-silico tools predict this variant to be damaging. An extensive array of functional studies have shown E3002K to significantly interfere with its HDR activity (Guidugli_Cancer Res_2012 and Mondal_Developmental Cell_2012) and ability to rescue BRCA2 -/- cells (Biswas_HMG_2012); additionally, E3002K disrupts interaction with Filamin A, localization of BRCA2 to the central spindle/midbody, and the integrity of cytokinesis (Mondal_Developmental Cell_2012). This variant was not found in 121072 control chromosomes; however, it has been reported to co-segregate with disease in multiple independent famlies. In addition, several clinical laboratories classified this variant as pathogenic/likely pathogenic. Taken together, this variant was classified as pathogenic.
Invitae RCV000195385 SCV000073698 pathogenic Hereditary breast and ovarian cancer syndrome 2018-12-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 3002 of the BRCA2 protein (p.Glu3002Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is not present in population databases (rs80359152, ExAC no frequency). This variant has been reported in the literature in individuals and families with breast and/or ovarian cancer (PMID: 20694749, 21947752, 25884701, 27223485). There is evidence of co-segregation with disease in affected families (PMID: 20694749, 21947752, 22678057). This variant is also known as c.9232G>A in the literature. ClinVar contains an entry for this variant (Variation ID: 38201). This variant is located in the C-terminal DNA-binding domain of BRCA2 protein (PMID: 22678057). Experimental studies have shown that this variant affects DNA repair activity, does not rescue BRCA2 function in BRCA2-deficient mouse embryonic stem cells, and affects cytokinesis (PMID: 23108138, 22678057, 22771033). For these reasons, this variant has been classified as Pathogenic.
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000195385 SCV000605787 pathogenic Hereditary breast and ovarian cancer syndrome 2017-07-20 criteria provided, single submitter clinical testing The p.Glu3002Lys variant in BRCA2 has been reported in >15 individuals with brea st or ovarian cancer and segregated with disease in 2 affected relatives from 1 family, including 1 obligate carrier (Salazar 2006, Cavallon 2010, Cote 2010, Be langer 2015, BIC database). It was also absent from large population studies. In vitro functional studies provide some evidence that the p.Glu3002Lys may impact protein function (Biswas 2012, Guidugli 2013). Computational prediction tools a nd conservation analysis suggest that the p.Glu3002Lys variant may impact the pr otein, though this information is not predictive enough to determine pathogenici ty. In summary, this variant meets criteria to be classified as pathogenic for h ereditary breast and ovarian cancer in an autosomal dominant manner based upon p roband count, segregation studies, absence from controls, functional evidence. A CMG/AMP Criteria applied: PS4, PM2, PS3_Moderate, PP1, PP3.
Michigan Medical Genetics Laboratories,University of Michigan RCV000031784 SCV000267825 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000045685 SCV000600836 pathogenic not provided 2015-12-03 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031784 SCV000054392 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
True Health Diagnostics RCV000130642 SCV000787958 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-24 no assertion criteria provided clinical testing

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