ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9004G>A (p.Glu3002Lys) (rs80359152)

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Total submissions: 18
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195385 SCV000073698 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-09 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.
Ambry Genetics RCV000130642 SCV000185521 likely pathogenic Hereditary cancer-predisposing syndrome 2020-09-25 criteria provided, single submitter clinical testing The p.E3002K variant (also known as c.9004G>A), located in coding exon 22 of the BRCA2 gene, results from a G to A substitution at nucleotide position 9004. The glutamic acid at codon 3002 is replaced by lysine, an amino acid with similar properties. This alteration has been identified in several unrelated families affected with breast, ovarian and/or pancreatic cancer, and has been reported to segregate with disease in at least two unrelated families (Salazar R et al. Cancer Lett. 2006 Feb;233(1):172-7; Cote S et al. Breast Cancer Res. Treat. 2012 Jan;131(1):333-40; Belanger MH et al. J. Ovarian Res. 2015 Mar;8:1; Pinto P et al. Breast Cancer Res. Treat. 2016 Sep;159:245-56; Gostimir M et al. BMC Cancer 2016 10;16(1):786; Cavallone L et al. Fam. Cancer 2010 Dec;9(4):507-17; Biswas K et al. Hum. Mol. Genet. 2012 Sep;21(18):3993-4006; Palmero EI et al. Sci Rep. 2018 Jun 15;8(1):9188). This alteration has been predicted to be likely deleterious by a protein likelihood ratio method and by multiple functional analyses (Karchin R et al. Cancer Inform. 2008 Apr;6:203-16; Biswas K et al. Hum. Mol. Genet. 2012 Sep;21(18):3993-4006; Mondal G et al. Dev. Cell 2012 Jul;23(1):137-52; Guidugli L et al. Cancer Res. 2013 Jan;73(1):265-75; Guidugli L et al. Am. J. Hum. Genet. 2018 Jan; Mesman RLS et al. Genet. Med. 2019 02;21:293-302). Of note, this alteration is also designated as 9232G>A in published literature. This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Based on the majority of available evidence to date, this variant is likely to be pathogenic.
GeneDx RCV000045685 SCV000210490 pathogenic not provided 2021-03-30 criteria provided, single submitter clinical testing Not observed in large population cohorts (Lek 2016); In silico analysis supports that this missense variant does not alter protein structure/function; Also known as 9232G>A; This variant is associated with the following publications: (PMID: 27724927, 24123850, 22632462, 25628955, 27553368, 22771033, 29387975, 25348012, 23704879, 12228710, 25884701, 21947752, 15876480, 26137147, 27223485, 19043619, 23108138, 20694749, 22678057, 25085752, 29108258, 28651617, 29161300, 29394989, 29988080, 18284688, 29907814, 30415210, 31131967, 29884841, 31447099)
Michigan Medical Genetics Laboratories,University of Michigan RCV000031784 SCV000267825 pathogenic Breast-ovarian cancer, familial 2 2016-04-21 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
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000045685 SCV000600836 pathogenic not provided 2020-03-06 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality. Found in at least one patient with expected phenotype for this gene. Predicted to have a damaging effect on the protein. Assessment of experimental evidence suggests this variant results in abnormal protein function. Segregation with disease in affected individuals from a single family.
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.
Color Health, Inc RCV000130642 SCV000684014 pathogenic Hereditary cancer-predisposing syndrome 2020-09-30 criteria provided, single submitter clinical testing This missense variant replaces glutamic acid with lysine at codon 3002 of the BRCA2 protein. Computational prediction suggests that this variant may have deleterious impact on protein structure and function (internally defined REVEL score threshold >= 0.7, PMID: 27666373). Functional studies have shown that this variant has defected homology-directed repair in vitro and fails to complement BRCA2-deficient cells (PMID: 22678057, 22771033, 23108138, 29394989, 29988080). This variant has been reported in individuals affected with breast/ovarian cancer (PMID: 20694749, 21947752, 22678057, 25884701, 27223485, 27553368, 29161300). This variant has not been identified in the general population by the Genome Aggregation Database (gnomAD). Based on the available evidence, this variant is classified as Pathogenic.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000195385 SCV000695199 pathogenic Hereditary breast and ovarian cancer syndrome 2019-01-24 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9004G>A (p.Glu3002Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 245586 control chromosomes (gnomAD). c.9004G>A has been reported in the literature in multiple affected individuals and has been shown to co-segregate with disease in multiple independent families (Biswas_2012, Cote_2012, Cavallone_2010). These data indicate that the variant is very likely to be associated with disease. An extensive array of functional studies have shown E3002K to significantly interfere with homology-directed DNA repair (HDR) activity (Guidugli_2012, Mondal_2012) and ability to rescue BRCA2 -/- cells (Biswas_2012); additionally, E3002K disrupts interaction with Filamin A, localization of BRCA2 to the central spindle/midbody, and the integrity of cytokinesis (Mondal_2012). Nine ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as pathogenic (6x) and likely pathogenic (3x). Based on the evidence outlined above, the variant was classified as pathogenic.
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.
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
Cancer Variant Interpretation Group UK, Institute of Cancer Research, London RCV000195385 SCV001478306 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-10-09 criteria provided, single submitter curation Data used in classification: The frequency of this variant is 0/138,632 individuals (gnomAD) (PM2_mod). This variant is predicted deleterious on AlignGVGD (class: C55), SIFT (Deleterious), Polyphen2 HumVar (probably damaging) and CADD (36) (PP3_sup). The variant is in the DNA-binding domain of BRCA2 (PM1_sup). In the BRCA2 Homology-Directed Repair Activity assay for the DNA Binding Domain (Guidugli et al Cancer Res 2013;73:265-275,Couch Lab), the variant has a probability of pathogenicity of 1.0 (PS3_strong). This variant is classified as pathogenic by 8 submitters on ClinVar, including by accredited USA diagnostic laboratories GeneDx (2018) and Color (2016) (PP5_sup). Data not used in classification: There are additional reports of this variant in ClinVar (5), UMD (3), BIC (9), and BRCA2 LOVD (2).
Research and Development, ARUP Laboratories RCV001642498 SCV001852822 uncertain significance Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Sharing Clinical Reports Project (SCRP) RCV000031784 SCV000054392 pathogenic Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000031784 SCV000147510 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353997 SCV000592246 likely pathogenic Malignant tumor of breast no assertion criteria provided clinical testing The p.Glu3002Lys variant has been reported in the literature in 10/2398 proband chromosomes of individuals with hereditary breast cancer. It was not, however, detected in any of the 200 control chromosomes tested (Biswas_2012, Cavallone_2010, Cote_2012, Mondal_2012, Salazar_2006). It has also been reported in the UMD (x2), LOVD, BIC (x9) and BOCs databases. It is listed in the dbSNP database (ID#:rs80359152) but no frequency information was provided, and so the prevalence of this variant in the general population is not known. The p.Glu3002 residue is conserved across mammals and computational analyses (PolyPhen, SIFT, AlignGVGD) suggest that the p.Glu3002Lys variant may impact the protein. However, this information is not predictive enough to assume pathogenicity. Yet, functional studies have shown that compared to the wild-type protein, the variant affects the integrity of cytokinesis during the cell cycle, and that the DNA repair capacity of the mutant allele is compromised (Biswas_2012, Mondal_2012). In summary, based on the above information, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as predicted pathogenic.
True Health Diagnostics RCV000130642 SCV000787958 likely pathogenic Hereditary cancer-predisposing syndrome 2018-01-24 no assertion criteria provided 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

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