ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1275A>G (p.Glu425=) (rs34355306)

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Total submissions: 20
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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) RCV000112901 SCV000245003 benign Breast-ovarian cancer, familial 2 2015-01-12 reviewed by expert panel curation Class 1 not pathogenic based on frequency >1% in an outbred sampleset. Frequency 0.01016 (African), derived from 1000 genomes (2012-04-30).
Invitae RCV001084122 SCV000071784 benign Hereditary breast and ovarian cancer syndrome 2020-12-07 criteria provided, single submitter clinical testing
Counsyl RCV000112901 SCV000154037 likely benign Breast-ovarian cancer, familial 2 2014-01-02 criteria provided, single submitter literature only
GeneDx RCV000173633 SCV000167330 benign not specified 2013-10-29 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 RCV000112901 SCV000195958 benign Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
Ambry Genetics RCV000162729 SCV000213195 benign Hereditary cancer-predisposing syndrome 2015-11-10 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.
EGL Genetic Diagnostics, Eurofins Clinical Diagnostics RCV000173633 SCV000224763 benign not specified 2014-12-11 criteria provided, single submitter clinical testing
Baylor Genetics RCV000458106 SCV000541051 benign Familial cancer of breast 2017-02-23 criteria provided, single submitter clinical testing
Genetic Services Laboratory, University of Chicago RCV000173633 SCV000593740 benign not specified 2017-06-20 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV000173633 SCV000602880 benign not specified 2019-03-05 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162729 SCV000683412 benign Hereditary cancer-predisposing syndrome 2015-04-08 criteria provided, single submitter clinical testing
PreventionGenetics,PreventionGenetics RCV000173633 SCV000805651 benign not specified 2017-07-11 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV001115061 SCV001273001 benign Fanconi anemia, complementation group D1 2019-05-06 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). No publications were found based on this search. Allele frequency data from public databases was too high to be consistent with this variant causing disease. Therefore, this variant is classified as benign.
Illumina Clinical Services Laboratory,Illumina RCV000112901 SCV001273002 benign Breast-ovarian cancer, familial 2 2019-05-06 criteria provided, single submitter clinical testing This variant was observed as part of a predisposition screen in an ostensibly healthy population. A literature search was performed for the gene, cDNA change, and amino acid change (where applicable). Publications were found based on this search. The evidence from the literature, in combination with allele frequency data from public databases where available, was sufficient to rule this variant out of causing disease. Therefore, this variant is classified as benign.
Breast Cancer Information Core (BIC) (BRCA2) RCV000112901 SCV000145844 benign Breast-ovarian cancer, familial 2 2010-09-18 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353996 SCV000591734 benign Malignant tumor of breast no assertion criteria provided clinical testing The BRCA2 p.Glu425Glu variant was identified in 29 of 2532 proband chromosomes (frequency: 0.011) from individuals or families with breast cancer, and was not identified in 334 control chromosomes from healthy individuals (Fackenthal 2012, Han 2006, Kawahara 2004, Toh 2008). The variant was also identified in dbSNP (ID: rs34355306) as “With Likely benign allele”, Clinvitae database (classified as benign by ClinVar and Invitae, as likely benign by ClinVar), the ClinVar database (classified as benign by ENIGMA, MMGLUM, Invitae, GeneDx, Emory genetics, BIC, as likely benign by Counsyl and Ambry genetics), the BIC database (2x with no clinical importance), UMD (70x with a “unclassified variant” classification) and Fanconi Anemia Mutation Database (LOVD). In UMD the variant was identified with a co-occurring pathogenic BRCA1 and BRCA2 variants (BRCA1: c.4986+6T>C, c.5468-2A>G and BRCA2: c.1310_1313delAAGA, p.Lys437IlefsX22), increasing the likelihood that the p.Glu425Glu variant does not have clinical significance. This variant was identified in the 1000 Genomes Project in 33 of 5000 chromosomes (frequency: 0.007), the NHLBI GO Exome Sequencing Project in 43 of 4400 African American alleles, the Exome Aggregation Consortium database (August 8, 2016) in 161 (2 homozygous) of 120508 chromosomes (freq. 0.001) in the following populations: African in 138 of 9866 chromosomes (freq. 0.01), East Asian in 20 of 8642 chromosomes (freq. 0.002), Latino in 3 of 11540 chromosomes (freq. 0.0003), increasing the likelihood this could be a low frequency benign variant. The p.Glu425Glu variant is not expected to have clinical significance because it does not result in a change of amino acid and is not located in a known consensus splice site. The variant occurs outside of the splicing consensus sequence and 1 of 5 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) predict a greater than 10% difference in splicing; this is not very predictive of pathogenicity. In summary, based on the above information, this variant meets our laboratory's criteria to be classified as benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000656586 SCV000778643 likely benign not provided 2017-10-09 no assertion criteria provided clinical testing
True Health Diagnostics RCV000162729 SCV000787918 likely benign Hereditary cancer-predisposing syndrome 2017-09-29 no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000173633 SCV001905780 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000173633 SCV001957559 benign not specified no assertion criteria provided clinical testing

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