ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.9976A>T (p.Lys3326Ter) (rs11571833)

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Total submissions: 38
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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) RCV000031849 SCV000244498 benign Breast-ovarian cancer, familial 2 2016-02-16 reviewed by expert panel curation Case-control and frequency data indicate that K3326X does not confer a high risk of cancer (OR 1.3-1.5, dependent on breast or ovarian cancer subtype).
Invitae RCV000045926 SCV000073939 benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Counsyl RCV000031849 SCV000154053 benign Breast-ovarian cancer, familial 2 2014-01-02 criteria provided, single submitter literature only
Ambry Genetics RCV000128910 SCV000172777 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing Intact protein function observed in appropriate functional assay(s);Other strong data supporting benign classification;Co-occurence with mutation in same gene (phase unknown);Co-occurence with a mutation in another gene that clearly explains a proband's phenotype;General population or subpopulation frequency is too high to be a pathogenic mutation based on disease/syndrome prevalence and penetrance;Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
Michigan Medical Genetics Laboratories,University of Michigan RCV000031849 SCV000196031 benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000120374 SCV000202309 benign not specified 2015-10-13 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000045926 SCV000212199 benign Hereditary breast and ovarian cancer syndrome 2015-03-11 criteria provided, single submitter research
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000735635 SCV000219429 likely benign Breast and/or ovarian cancer 2017-12-19 criteria provided, single submitter clinical testing
Division of Genomic Diagnostics,The Children's Hospital of Philadelphia RCV000045926 SCV000257622 benign Hereditary breast and ovarian cancer syndrome 2015-07-09 criteria provided, single submitter clinical testing
Color RCV000128910 SCV000292115 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000120374 SCV000301783 benign not specified criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000031849 SCV000383808 likely benign Breast-ovarian cancer, familial 2 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000034474 SCV000511377 benign not provided 2016-12-27 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000031849 SCV000575759 benign Breast-ovarian cancer, familial 2 2016-02-22 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000120374 SCV000586993 benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000120374 SCV000588130 benign not specified 2017-04-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120374 SCV000592309 likely benign not specified 2015-11-30 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000120374 SCV000602758 benign not specified 2018-08-14 criteria provided, single submitter clinical testing
GeneKor MSA RCV000120374 SCV000693648 benign not specified 2017-11-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000034474 SCV000695284 benign not provided 2016-08-12 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.9976A>T (p.Lys3326X) variant results in a termination codon at the penultimate exon, predicted to cause a truncation of the last 93 amino acids. This variant is not expected to affect any known domain (InterPro) and no truncations downstream of this position have been reported to be pathogenic in literature and databases. This variant was found in 2327/296226 control chromosomes (including 8 homozygotes) at a frequency of 0.0078555, which is approximately 10 times the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503), suggesting this variant is likely a benign polymorphism. In addition, several clinical diagnostic laboratories/reputable databases have classified this variant as benign (14)/likely benign (1). Available family, co-occurrence and functional data also show that it is not a disease causing variant. Despite these, this variant is found at considerably high frequency, especially in patients with breast and/or ovarian cancer, raising a possibilty that it may be a risk variant. Using weighted logistic regression, Meeks et al 2016 analyzed data from the large iCOGS study including 76637 cancer case patients and 83796 control patients to estimate odds ratios (ORw) and 95% confidence intervals (CIs) for K3326X variant carriers in relation to breast, ovarian, and prostate cancer risks, with weights defined as probability of not having a pathogenic BRCA2 variant. Other adjustments in the study were adjustment for attained age, consortium study site, and principal components of population structure. From the study, weighted ORs for invasive breast cancer and ovarian cancers were 1.28 (confidence interval 1.17-1.4; P-value=3.84x10e-3) and 1.26 (confidence interval 1.1-1.43; P-value=3.84x10e-3), respectively. The authors conclude that this study provides evidence that the K3326X variant is associated with risk of developing breast and ovarian cancers independent of other pathogenic variants in BRCA2. Hence this variant is a risk allele which attributes a significant but a low risk in development of breast or ovarian cancer. In addition, other genetic/lifestyle/environmental factors may also be playing a part in elevation of risk. Taken together, this variant is classified as Benign for HBOC.
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031849 SCV000743529 benign Breast-ovarian cancer, familial 2 2014-10-09 criteria provided, single submitter clinical testing
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031849 SCV000744794 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Mendelics RCV000031849 SCV001139281 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034474 SCV001149001 likely benign not provided 2018-06-01 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001112896 SCV001270610 likely benign Fanconi anemia, complementation group D1 2018-03-06 criteria provided, single submitter clinical testing This variant was observed in the ICSL laboratory as part of a predisposition screen in an ostensibly healthy population. It had not been previously curated by ICSL or reported in the Human Gene Mutation Database (HGMD: prior to June 1st, 2018), and was therefore a candidate for classification through an automated scoring system. Utilizing variant allele frequency, disease prevalence and penetrance estimates, and inheritance mode, an automated score was calculated to assess if this variant is too frequent to cause the disease. Based on the score and internal cut-off values, a variant classified as likely benign is not then subjected to further curation. The score for this variant resulted in a classification of likely benign for this disease.
Institute of Human Genetics, University of Leipzig Medical Center RCV000031849 SCV001429528 uncertain significance Breast-ovarian cancer, familial 2 2017-09-21 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034474 SCV000043239 no known pathogenicity not provided 2012-07-13 no assertion criteria provided research Converted during submission to Benign.
Sharing Clinical Reports Project (SCRP) RCV000031849 SCV000054457 benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing
ITMI RCV000120374 SCV000084526 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000031849 SCV000145737 benign Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000031849 SCV000187732 likely benign Breast-ovarian cancer, familial 2 2014-07-24 no assertion criteria provided literature only
GeneReviews RCV000031849 SCV000484958 pathogenic Breast-ovarian cancer, familial 2 2016-12-15 no assertion criteria provided literature only
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000120374 SCV000588018 benign not specified 2014-01-31 no assertion criteria provided research
Diagnostic Laboratory, Department of Genetics,University Medical Center Groningen RCV000031849 SCV000733342 benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Mayo Clinic Genetic Testing Laboratories,Mayo Clinic RCV000034474 SCV000778727 likely benign not provided 2017-02-02 no assertion criteria provided clinical testing
True Health Diagnostics RCV000128910 SCV000787962 benign Hereditary cancer-predisposing syndrome 2018-02-20 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735635 SCV000863773 likely benign Breast and/or ovarian cancer 2013-08-02 no assertion criteria provided clinical testing
Center of Medical Genetics and Primary Health Care RCV001004846 SCV000987251 benign breast cancer 2020-04-08 no assertion criteria provided research ACMG Guidelines 2015 criteria

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