ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.1561G>A (p.Ala521Thr)

gnomAD frequency: 0.00019  dbSNP: rs80357122
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Total submissions: 12
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195389 SCV000075536 likely benign Hereditary breast ovarian cancer syndrome 2021-12-08 criteria provided, single submitter clinical testing
Ambry Genetics RCV000130445 SCV000185309 likely benign Hereditary cancer-predisposing syndrome 2018-10-29 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other data supporting benign classification
GeneDx RCV000586560 SCV000210104 likely benign not provided 2021-01-04 criteria provided, single submitter clinical testing In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function; Observed in individuals with personal and/or family history of breast and/or ovarian cancer (Olopade 2003, Russo 2007); This variant is associated with the following publications: (PMID: 24728327, 12491487, 17221156, 25348012, 15385441, 28873162, 10923033)
Counsyl RCV000111646 SCV000488128 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2016-02-19 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000120288 SCV000600257 uncertain significance not specified 2016-08-24 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000120288 SCV000698875 likely benign not specified 2020-11-04 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.1561G>A (p.Ala521Thr) 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, a finding consistent with other in-silico studies reporting a neutral outcome (example, Martelotto_2014, Pavlicek_2004). The variant allele was found at a frequency of 4.8e-05 in 250464 control chromosomes, predominantly at a frequency of 0.00068 within the African or African-American subpopulation in the gnomAD database. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (4.8e-05 vs 0.001), allowing no conclusion about variant significance. c.1561G>A has been reported in the literature in individuals affected with Breast and/or Ovarian Cancer (example, Olopade_2003, Russo_2007). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Seven 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 (likely benign, n=3, VUS, n=4). At-least one submitter has re-classified this variant from a VUS to likely benign since its previous evaluation reflecting a possible emerging consensus towards a likely benign outcome. Based on the absence of concrete evidence supporting an actionable outcome spanning over 5 years of testing and literature review as outlined above, the variant was re-classified as likely benign.
Color Diagnostics, LLC DBA Color Health RCV000130445 SCV000903013 likely benign Hereditary cancer-predisposing syndrome 2015-11-17 criteria provided, single submitter clinical testing
Division of Medical Genetics, University of Washington RCV000111646 SCV001424778 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2019-02-19 criteria provided, single submitter clinical testing This variant has been reported in individuals with breast cancer and ovarian cancer (Olopade 2003, Russo 2007), as well as healthy individuals of African ancestry (Bodian 2014). The c.1561G>A variant has an overall allele frequency of 0.00005 in the Genome Aggregation Database (gnomad.broadinstitute.org). Thus, it is unknown at this time whether this variant increases cancer risk.
Genetic Services Laboratory,University of Chicago RCV000120288 SCV002071354 uncertain significance not specified 2019-11-08 criteria provided, single submitter clinical testing
ITMI RCV000120288 SCV000084440 not provided not specified 2013-09-19 no assertion provided reference population
Breast Cancer Information Core (BIC) (BRCA1) RCV000111646 SCV000144131 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000586560 SCV001551718 uncertain significance not provided no assertion criteria provided clinical testing

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