ClinVar Miner

Submissions for variant NM_000059.4(BRCA2):c.4585G>A (p.Gly1529Arg) (rs28897728)

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Total submissions: 27
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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) RCV000113324 SCV000244450 benign Breast-ovarian cancer, familial 2 2015-08-10 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 = 0.000000000166
Invitae RCV000044446 SCV000072459 benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
Counsyl RCV000113324 SCV000154094 benign Breast-ovarian cancer, familial 2 2014-04-02 criteria provided, single submitter literature only
GeneDx RCV000656605 SCV000210607 likely benign not provided 2020-10-23 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 19471317, 11447276, 11873550, 26332594, 28651617, 28324225, 24323938, 25896959, 20694749, 22811390, 24055113, 21520273, 25637381, 25782689, 23231788, 20104584, 23034506, 15983021, 10551859, 19747923, 12442171, 21990134, 27741520, 27153395, 27376475, 28283652, 17924331, 29356034, 32426482, 32846166)
Ambry Genetics RCV000162670 SCV000213117 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.
Pathway Genomics RCV000113324 SCV000223766 likely benign Breast-ovarian cancer, familial 2 2014-10-30 criteria provided, single submitter clinical testing
Michigan Medical Genetics Laboratories,University of Michigan RCV000113324 SCV000267766 likely benign Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Illumina Clinical Services Laboratory,Illumina RCV000353459 SCV000383702 likely benign Fanconi anemia, complementation group D1 2019-09-23 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 allowed determination this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Illumina Clinical Services Laboratory,Illumina RCV000113324 SCV000383703 likely benign Breast-ovarian cancer, familial 2 2019-09-23 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 determine this variant is unlikely to cause disease. Therefore, this variant is classified as likely benign.
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044446 SCV000494387 benign Hereditary breast and ovarian cancer syndrome 2015-04-06 criteria provided, single submitter clinical testing Variant summary: The variant of interest causes a missense change in a conserved position with 4/4 in silico programs predicting a "deleterious" outcome (SNPs&Go not captured here due to low reliability index). The variant of interest has an observed allele frequency of 57/121370 (1/2127) in controls, which does not significantly exceed the maximum expect allele frequency for a pathogenic BRCA2 variant, 1/1333. However, the variant of interest has been found in cases to co-occur with multiple potential pathogenic BRCA2 (1 - c.5350_5351delAA (p.Asn1784HisfsX2) and 1 - c.8755_10257del (p.Gly2919fsX15)) and BRCA1 (1 - c.3226A>T (p.Arg1076X)) variants including internal LCA sample that co-occurred with a BRCA1 variant, c.3358_3359delGT (p.Val1120X scored DV). Although, functional studies show no impairment on exon splicing but conflicting evidence for a role in homologous recombination via recruitment of RAD51, however, this functional analysis has not been indepdently reproduced by other laboratories and their relevance to in-vivo mechanisms of pathogenicity have not been unequivocally established. Furthermore, multiple reputable databases (ARUP, UMD, BIC, SCRP, GeneDx and Ambry Genetics) and publications (Easton_2007 and Lindor_2012) classify the variant as likely benign/benign/neutral. . Therefore, taken together, the variant of interest is classified as benign.
Laboratory for Molecular Medicine, Partners HealthCare Personalized Medicine RCV000160225 SCV000538486 uncertain significance not specified 2016-03-28 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: ExAC: 0.1%(42/66226) European; ClinVar: 8 B/LB
ARUP Laboratories, Molecular Genetics and Genomics,ARUP Laboratories RCV001282554 SCV000602833 likely benign none provided 2020-02-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000162670 SCV000683634 likely benign Hereditary cancer-predisposing syndrome 2015-04-02 criteria provided, single submitter clinical testing
Genome Diagnostics Laboratory, University Medical Center Utrecht RCV000113324 SCV000743301 likely benign Breast-ovarian cancer, familial 2 2015-06-15 criteria provided, single submitter clinical testing
Clinical Genetics DNA and cytogenetics Diagnostics Lab, Erasmus MC, Erasmus Medical Center RCV000113324 SCV000744459 benign Breast-ovarian cancer, familial 2 2015-09-21 criteria provided, single submitter clinical testing
Mendelics RCV000113324 SCV001139093 likely benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
St. Jude Clinical Genomics Lab, St. Jude Children's Research Hospital RCV000044446 SCV001775532 benign Hereditary breast and ovarian cancer syndrome 2021-08-04 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642341 SCV001854804 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
Sharing Clinical Reports Project (SCRP) RCV000113324 SCV000054096 benign Breast-ovarian cancer, familial 2 2011-03-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113324 SCV000146453 benign Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CSER _CC_NCGL, University of Washington RCV000148413 SCV000190112 likely benign Breast and/or ovarian cancer 2014-06-01 no assertion criteria provided research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000656605 SCV000591912 likely benign not provided no assertion criteria provided clinical testing The BRCA2 p.Gly1529Arg variant was identified in 4 of 6448 proband chromosomes (frequency: 0.001) from individuals with breast or ovarian cancer (Borg 2010, Kauff 2008, Sinclair 2002). Two functional studies suggest that the variant affects binding with Rad51 (Chen 1999, Tal 2009), and one in silico study predicts that this variant may be deleterious using hierarchal modeling (Capanu 2011). However, there is conflicting evidence, two additional in silico studies using multifactorial-likelihood ratio models predict the variant to be neutral (Easton 2007, Lindor 2012). The variant was identified in dbSNP (ID: rs28897728) as “With Likely benign allele”, in Clinvitae database (classifications; benign and likely benign), Fanconi Anemia Mutation Database (LOVD), LOVD-IARC database, ARUP Laboratories BRCA Mutations Database (classified as not pathogenic, of no clinical importance), COSMIC (in a medulloblastoma and endometrioid carcinoma), the ClinVar database (classification benign, reviewed by an expert panel, multiple submitters), GeneInsight COGR database (classifications of likely benign, benign, and uncertain significance by 4 clinical laboratories), the BIC database (75x with no clinical importance), and UMD (62x with a “neutral” classification, co-occurring with deleterious BRCA1, c.3226A>T, p.Arg1076X, BRCA2, c.5350_5351delAA, p.Asn1784HisfsX2, and BRCA2, c.8755_10257del, p.Gly2919fsx15 variants, increasing the likelihood that the p.Gly1529Arg variant does not have clinical significance. The variant was also identified in the 1000 Genomes Project in 3 of 5000 chromosomes (frequency: 0.0006), HAPMAP populations -EUR in 2 of 1006 chromosomes (frequency: 0.002) and AMR in 1 of 694 chromosomes (frequency: 0.0014), NHLBI GO Exome Sequencing Project in 6 of 8600 European American alleles (frequency: 0.0007), and the Exome Aggregation Consortium (March 14, 2016) in 51 of 120448 chromosomes (freq. 0.00042) in the following populations: European (Non-Finnish) in 42 of 66226 chromosomes (freq. 0.00063), South Asian in 6 of 16482 chromosomes (freq. 0.00036), Latino in 2 of 11536 chromosomes (freq. 0.00017), and other in 1 of 898 chromosomes (freq. 0.00011) but was not seen in African, East Asian, and Finnish populations. The p.Gly1529 residue is conserved across mammals and lower organisms and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, Mutation Taster) suggest that the p.Gly1529Arg variant may impact the protein however this information is not predictive enough to assume pathogenicity. 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, the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more benign role for this variant. This variant is classified as likely benign.
Mayo Clinic Laboratories, Mayo Clinic RCV000656605 SCV000778676 likely benign not provided 2015-10-07 no assertion criteria provided clinical testing
True Health Diagnostics RCV000162670 SCV000787932 likely benign Hereditary cancer-predisposing syndrome 2017-09-11 no assertion criteria provided clinical testing
Laboratory of Diagnostic Genome Analysis, Leiden University Medical Center (LUMC) RCV000160225 SCV001799991 benign not specified no assertion criteria provided clinical testing
Clinical Genetics Laboratory, Department of Pathology,Netherlands Cancer Institute RCV000160225 SCV001905956 benign not specified no assertion criteria provided clinical testing
Human Genetics - Radboudumc,Radboudumc RCV000160225 SCV001958662 benign not specified no assertion criteria provided clinical testing

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