ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.823G>A (p.Gly275Ser) (rs8176153)

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Total submissions: 11
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000225768 SCV000077171 benign not provided 2018-11-07 criteria provided, single submitter clinical testing
Ambry Genetics RCV000132245 SCV000187328 likely benign Hereditary cancer-predisposing syndrome 2017-12-19 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Seen in trans with a mutation or in homozygous state in individual without severe disease for that gene
GeneDx RCV000049158 SCV000210090 likely benign not specified 2018-01-12 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.
Counsyl RCV000112797 SCV000488322 likely benign Breast-ovarian cancer, familial 1 2016-03-03 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000049158 SCV000586872 likely benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Color RCV000132245 SCV000683369 likely benign Hereditary cancer-predisposing syndrome 2016-02-09 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000049158 SCV000699314 likely benign not specified 2019-08-16 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.823G>A (p.Gly275Ser) results in a non-conservative amino acid change in the encoded protein sequence. Three of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 0.00056 in 250402 control chromosomes, predominantly at a frequency of 0.0046 within the South Asian subpopulation in the gnomAD database, including 2 homozygotes. The observed variant frequency within South Asian control individuals in the gnomAD database is approximately 4.6 fold of the estimated maximal expected allele frequency for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer phenotype (0.001), strongly suggesting that the variant is a benign polymorphism found primarily in populations of South Asian origin. c.823G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer, primarily in individuals of South Asian ethnicity (Vinodkumar_2007, Ahmad_2012, Juwle_2012, Sirisena_2016). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. A large case-control study performed on a multiethnic Asian cohort found there was no association with this variant and increased breast cancer risk (Lai 2017). Co-occurrence with another pathogenic variant has been reported (UMD Database: BRCA2 c.2612C>A, p.Ser871X), providing supporting evidence for a benign role. At least one publication reports experimental evidence evaluating an impact on protein function, however, does not allow convincing conclusions about the variant effect (Starita_2015). Six clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as benign/likely benign. Based on the evidence outlined above, the variant was classified as likely benign.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000225768 SCV001133653 benign not provided 2019-04-20 criteria provided, single submitter clinical testing
Mendelics RCV000112797 SCV001140619 benign Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112797 SCV000145694 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing
Pathway Genomics RCV000112797 SCV000207336 likely benign Breast-ovarian cancer, familial 1 2014-11-06 no assertion criteria provided clinical testing

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