ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9038C>T (p.Thr3013Ile) (rs28897755)

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Total submissions: 20
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000034471 SCV000883501 likely benign not provided 2018-02-02 criteria provided, single submitter clinical testing The BRCA2 c.9038C>T; p.Thr3013Ile variant (rs28897755) has been reported in the literature in individuals with a personal or family history of hereditary breast and ovarian cancer (Houdayer 2012, Malone 2000, Sanz 2010). However, this variant has also been found incidentally in an individual with no personal or family history of cancer (Johnston 2012). This variant is reported with conflicting interpretations of pathogenicity in ClinVar, with most sources classifying as benign or likely benign (Variation ID: 38205) and is seen in the general population at an overall frequency of 0.02% (65/276280 alleles, including 1 homozygote) in the Genome Aggregation Database. The threonine at codon 3013 is moderately conserved but computational algorithms (SIFT, PolyPhen2, MutationTaster) predict this variant to have no impact on protein function. In agreement with this, functional analysis of this variant protein shows no defects in DNA double-strand break repair using a cell-based homology directed repair assay (Guidugli 2013). Based on the above information, this variant is considered likely benign. REFERENCES 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): 265–275. Houdayer C et al. Guidelines for splicing analysis in molecular diagnosis derived from a set of 327 combined in silico/in vitro studies on BRCA1 and BRCA2 variants. Hum Mutat. 2012 Aug;33(8):1228-38. Johnston J et al. Secondary Variants in Individuals Undergoing Exome Sequencing: Screening of 572 Individuals Identifies High-Penetrance Mutations in Cancer-Susceptibility Genes. Am J Hum Genet. 2012 Jul 13; 91(1): 97–108. Malone K et al. Frequency of BRCA1/BRCA2 mutations in a population-based sample of young breast carcinoma cases. Cancer. 2000 Mar 15;88(6):1393-402. Sanz D 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.
Ambry Genetics RCV000131061 SCV000185991 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034471 SCV000043237 probably not pathogenic not provided 2012-07-13 no assertion criteria provided research Converted during submission to Likely benign.
Breast Cancer Information Core (BIC) (BRCA2) RCV000031788 SCV000147519 benign Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000768639 SCV000219417 likely benign Breast and/or ovarian cancer 2017-08-31 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148415 SCV000190114 likely benign Neoplasm of the breast 2014-06-01 no assertion criteria provided research
Center for Pediatric Genomic Medicine,Children's Mercy Hospital and Clinics RCV000034471 SCV000609923 likely benign not provided 2017-06-20 criteria provided, single submitter clinical testing
Color RCV000131061 SCV000684018 likely benign Hereditary cancer-predisposing syndrome 2015-03-09 criteria provided, single submitter clinical testing
Counsyl RCV000031788 SCV000220479 likely benign Breast-ovarian cancer, familial 2 2014-07-03 criteria provided, single submitter literature only
DNA and Cytogenetics Diagnostics Unit,Erasmus Medical Center RCV000031788 SCV000744553 benign Breast-ovarian cancer, familial 2 2017-05-31 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000454455 SCV000592250 benign not specified 2013-10-25 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory,University Medical Center Utrecht RCV000031788 SCV000743357 benign Breast-ovarian cancer, familial 2 2014-10-09 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000347597 SCV000383799 likely benign Fanconi anemia 2016-06-14 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000045695 SCV000383800 likely benign Hereditary breast and ovarian cancer syndrome 2016-06-14 criteria provided, single submitter clinical testing
Institute for Biomarker Research,Medical Diagnostic Laboratories, L.L.C. RCV000131061 SCV000803164 likely benign Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing
Invitae RCV000045695 SCV000073708 benign Hereditary breast and ovarian cancer syndrome 2017-12-27 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare Personalized Medicine RCV000454455 SCV000538499 uncertain significance not specified 2016-06-23 criteria provided, single submitter clinical testing Variant identified in a genome or exome case(s) and assessed due to predicted null impact of the variant or pathogenic assertions in the literature or databases. Disclaimer: This variant has not undergone full assessment. The following are preliminary notes: ClinVar: 8 B/LB
PreventionGenetics RCV000454455 SCV000805791 benign not specified 2017-11-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031788 SCV000054396 benign Breast-ovarian cancer, familial 2 2006-03-15 no assertion criteria provided clinical testing
True Health Diagnostics RCV000131061 SCV000787959 likely benign Hereditary cancer-predisposing syndrome 2017-09-07 no assertion criteria provided clinical testing

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