ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.8182G>A (p.Val2728Ile) (rs28897749)

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Total submissions: 35
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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) RCV000113882 SCV001161619 benign Breast-ovarian cancer, familial 2 2019-06-18 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 1 based on posterior probability = 0.000345
Invitae RCV000045443 SCV000073456 benign Hereditary breast and ovarian cancer syndrome 2020-12-08 criteria provided, single submitter clinical testing
Counsyl RCV000113882 SCV000154049 likely benign Breast-ovarian cancer, familial 2 2014-01-02 criteria provided, single submitter literature only
GeneDx RCV000120362 SCV000167408 benign not specified 2013-10-21 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Michigan Medical Genetics Laboratories,University of Michigan RCV000113882 SCV000196012 benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000120362 SCV000202302 benign not specified 2014-02-10 criteria provided, single submitter clinical testing
CSER _CC_NCGL, University of Washington RCV000045443 SCV000212197 benign Hereditary breast and ovarian cancer syndrome 2015-03-11 criteria provided, single submitter research
Ambry Genetics RCV000162583 SCV000212999 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Vantari Genetics RCV000162583 SCV000267025 benign Hereditary cancer-predisposing syndrome 2016-01-22 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000113882 SCV000383779 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.
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034462 SCV000493633 likely benign not provided 2020-04-01 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000045443 SCV000494363 benign Hereditary breast and ovarian cancer syndrome 2014-09-24 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000120362 SCV000586980 benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000120362 SCV000593731 likely benign not specified 2016-07-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001281868 SCV000602816 benign none provided 2020-08-20 criteria provided, single submitter clinical testing
Institute for Biomarker Research, Medical Diagnostic Laboratories, L.L.C. RCV000162583 SCV000679725 likely benign Hereditary cancer-predisposing syndrome 2017-07-12 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162583 SCV000683949 benign Hereditary cancer-predisposing syndrome 2014-11-22 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000113882 SCV000743345 benign Breast-ovarian cancer, familial 2 2014-10-09 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000113882 SCV000744537 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000034462 SCV000805775 likely benign not provided 2017-02-20 criteria provided, single submitter clinical testing
Mendelics RCV000113882 SCV001139208 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001114098 SCV001271931 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.
Research and Development, ARUP Laboratories RCV001642549 SCV001852781 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034462 SCV000043229 probably not pathogenic not provided 2012-07-13 no assertion criteria provided research Converted during submission to Likely benign.
ITMI RCV000120362 SCV000084514 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA2) RCV000113882 SCV000147293 benign Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Pathway Genomics RCV000113882 SCV000187731 likely benign Breast-ovarian cancer, familial 2 2014-07-24 no assertion criteria provided literature only
CSER _CC_NCGL, University of Washington RCV000148414 SCV000190113 likely benign Breast neoplasm 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353716 SCV000592177 benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Val2728Ile variant was identified in 26 of 7026 proband chromosomes (frequency: 0.004) from individuals or families with breast, prostate or melanoma cancers, and was present in 4 of 1852 control chromosomes (frequency: 0.002) from healthy individuals (Sinilnikova 1999, Diez 2003, Haffy 2006, Luedeke 2009, Capanu 2011, Kuusisto 2011, Stegel 2011). The variant was identified by our laboratory in 2 individuals with breast cancer. The variant was also identified in dbSNP (ID: rs28897749 “With Other, untested allele”, in NHLBI Exome Sequencing Project (Exome Variant Server) in 39 of 8600 European American and 4 of 4406 African American; in HAPMAP-CEU in 2 of 224 chromosomes (frequency: 0.009) and in HAPMAP-MEX in 3 of 98 chromosomes(frequency: 0.031). In Exome Aggregation Consortium (ExAC) database the variant is found in 216 of 66738 (I homozygote) European (Non-Finnish), 18 of 6614 European (Finnish), 10 of 10404 African, 2 of 11576 Latino and 1 in 908 in Other alleles, increasing the likelihood this could be a low frequency benign variant. The variant was not found in East Asian and South Asian. The variant was identified in LOVD (7x predicted neutral), the ClinVar database (classified as a Benign variant by Invitae (Jun26, 2015), GeneDx (Oct21, 2013), Emory Genetics (Feb10, 2014), Ambry Genetics (Nov19, 2014), Molecular Genetics Diagnostic-CHEO, BIC (May29, 2002) and as Likely Benign by Counsyl (Jan02, 2014), Pathway Genomics (Jul24, 2014), CSER-University of Washington (Jun01, 2014), Biesecker Lab ClinSeq Project (Jul13, 2012); no classification was provided by ITMI. The variant was reported in GeneInsight through the Canadian Open Genetics Repository (http://opengenetics.ca/) (2X, classified as “benign” by 2 clinical laboratories), the BIC database (92X with NO clinical importance), and UMD (95X as a neutral variant). In UMD the variant was identified with a co-occurring pathogenic BRCA2:c.1257delT (p.Cys419TrpfsX11), c.7230delT (p.Phe2410LeufsX59), c.6209_6212delAAAG (p.Glu2070ValfsX10), and BRCA1:c.5123C>A (p.Ala1708Glu), c.2308delT (p.Ser770HisfsX22), c.4065_4068delTCAA (p.Asn1355LysfsX10), c.5137delG (p.Val1713X), increasing the likelihood that the p.Val2728Ile variant does not have clinical significance. In addition, Myriad classifies this as a polymorphism (personal communication). The Val2728 residue is not conserved in mammals and computational analyses (SIFT, AlignGVGD) do not predict any effect on the protein function. In addition, the variant amino acid Ile (isoleucine) is present in other mammals and lower organisms increasing the likelihood that this variant does not have clinical significance. Overrepresentation of this variant had conferred 2.3-fold increased risk for sporadic prostate cancer and a 6-fold increased risk for familial prostate cancers, however larger sample sizes and replication studies are necessary to clarify the role of the variant in prostate cancer (Luedeke 2009). The c.8182G>A variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information, we lean towards a more benign role for this variant. This variant is classified as Benign.
Diagnostic Laboratory, Department of Genetics, University Medical Center Groningen RCV000113882 SCV000733316 benign Breast-ovarian cancer, familial 2 no assertion criteria provided clinical testing
Mayo Clinic Laboratories, Mayo Clinic RCV000034462 SCV000778718 benign not provided 2017-03-08 no assertion criteria provided clinical testing
True Health Diagnostics RCV000162583 SCV000787953 likely benign Hereditary cancer-predisposing syndrome 2017-11-14 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000034462 SCV001799045 likely benign not provided no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000120362 SCV001906143 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000120362 SCV001956346 benign not specified no assertion criteria provided clinical testing

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