ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1568A>G (p.His523Arg) (rs80358443)

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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132044 SCV000187104 likely benign Hereditary cancer-predisposing syndrome 2018-12-28 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000160205 SCV000210563 likely benign not specified 2018-02-28 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.
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240762 SCV000265928 uncertain significance Breast neoplasm 2015-11-01 criteria provided, single submitter research
Invitae RCV001088277 SCV000283170 benign Hereditary breast and ovarian cancer syndrome 2019-12-31 criteria provided, single submitter clinical testing
Color RCV000132044 SCV000537501 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Fulgent Genetics,Fulgent Genetics RCV000082887 SCV000575722 uncertain significance Breast-ovarian cancer, familial 2 2015-08-07 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000160205 SCV000591754 likely benign not specified 2016-06-02 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000160205 SCV000694546 benign not specified 2019-09-16 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1568A>G (p.His523Arg) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 0.00013 in 246858 control chromosomes, predominantly at a frequency of 0.0015 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 2 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA2 causing Hereditary Breast and Ovarian Cancer phenotype (0.00075), strongly suggesting that the variant is a benign polymorphism found primarily in populations of East Asian origin. c.1568A>G has been reported in the literature predominantly among individuals of East Asian ancestry affected with Hereditary Breast and Ovarian Cancer (Cao_2016, Coulet_2010, Dong_2015, Coulet_2010, Park_2016,Seong_2009, Suter_2004, Zhong_2011, Zhong_2016, Bhaskaran_2019, Dong_2018). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported in the literature as well as our own laboratory (BRCA2 c.2175dup, p.Val726fs (Dong_2015); BRCA1 c.5521delA, p.Ser1841fs (Dong_2018); and our laboratory, BRCA1 c.3770_3771delAG, p.Glu1257fsX9), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Nine clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments predominantly as likely benign/benign (Benign, n=1; Likely benign, n=6; uncertain significance, n=2). At-least one submitter has downgraded this variant from its previous classification of Likely benign to Benign. Based on the evidence outlined above, the variant was re-classified as benign.
3DMed Clinical Laboratory Inc RCV000240762 SCV000804016 likely benign Breast neoplasm 2018-05-21 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677856 SCV000804017 likely benign Cancer of the pancreas 2018-05-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000590104 SCV000888982 likely benign not provided 2018-03-10 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082887 SCV000114961 likely benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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