ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7522G>A (p.Gly2508Ser) (rs80358978)

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Total submissions: 16
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000203651 SCV000073249 benign not provided 2019-02-28 criteria provided, single submitter clinical testing
GeneDx RCV000120359 SCV000210654 likely benign not specified 2017-12-07 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.
Ambry Genetics RCV000164682 SCV000215349 uncertain significance Hereditary cancer-predisposing syndrome 2019-02-14 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Laboratory of Molecular Diagnosis of Cancer,West China Hospital, Sichuan University RCV000240741 SCV000265956 uncertain significance Neoplasm of the breast 2015-11-01 criteria provided, single submitter research
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000120359 SCV000592120 uncertain significance not specified 2016-07-15 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000120359 SCV000602837 uncertain significance not specified 2016-12-06 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000120359 SCV000695074 likely benign not specified 2019-01-09 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7522G>A (p.Gly2508Ser) variant involves the alteration of a conserved nucleotide located in the helical domain (via InterPro). Five of five in-silico tools predict a damaging effect of the variant on protein function. The impact of the Gly2508Ser variant on BRCA2 function was evaluated using biochemical and cell-based homology-directed repair (HDR) assays, and the functional results suggest a mild impact on BRCA2 activity (Shimelis_2017, Mesman_2018, Guidugli_2018). The variant allele was found at a frequency of 0.0002 in 304670 control chromosomes, predominantly at a frequency of 0.0022 within the East Asian subpopulation in the gnomAD database. The observed variant frequency within East Asian control individuals in the gnomAD database is approximately 3-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. The variant, c.7522G>A, has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, without strong evidence for causality (Liang_2018, Zhong_2016, Park_2017, Ng_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. However, a large case-control study, Han_2017, found the variant to have a strong association with BrC in Asians ((OR (95%CI) of 3.02 (1.69-5.39) and p-value = 0.000123)). Co-occurrences with other pathogenic variants have been reported (BRCA2 c.8340_8343delTAAC, p.Asn2781Valfs; BRCA1 3746insA, p.Glu1210Argfs), providing supporting evidence for a benign role. Nine other 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 (VUS x7, likely benign/benign x2). Based on the evidence outlined above and considering the functional implications and positive association with risk for BrC, the variant was classified as likely benign.
3DMed Clinical Laboratory Inc RCV000677860 SCV000804021 uncertain significance Infiltrating duct carcinoma of breast 2017-07-21 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677861 SCV000804022 uncertain significance Ovarian cancer 2017-07-21 criteria provided, single submitter clinical testing
3DMed Clinical Laboratory Inc RCV000677862 SCV000804023 uncertain significance Cancer of the pancreas 2017-07-21 criteria provided, single submitter clinical testing
Color RCV000164682 SCV000910752 likely benign Hereditary cancer-predisposing syndrome 2016-11-13 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000203651 SCV001133904 likely benign not provided 2018-12-12 criteria provided, single submitter clinical testing
Mendelics RCV000077404 SCV001139184 benign Breast-ovarian cancer, familial 2 2019-05-28 criteria provided, single submitter clinical testing
ITMI RCV000120359 SCV000084511 not provided not specified 2013-09-19 no assertion provided reference population
Sharing Clinical Reports Project (SCRP) RCV000077404 SCV000109201 likely benign Breast-ovarian cancer, familial 2 2008-10-07 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077404 SCV000147112 uncertain significance Breast-ovarian cancer, familial 2 2004-02-20 no assertion criteria provided clinical testing

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