ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.427G>A (p.Glu143Lys)

gnomAD frequency: 0.00004  dbSNP: rs80356991
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Total submissions: 15
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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) RCV000031161 SCV000244359 benign Breast-ovarian cancer, familial, susceptibility to, 1 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 = 0.0000109
Invitae RCV000588563 SCV000076523 likely benign Hereditary breast ovarian cancer syndrome 2024-01-29 criteria provided, single submitter clinical testing
GeneDx RCV001719704 SCV000210075 likely benign not provided 2021-02-09 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; This variant is associated with the following publications: (PMID: 11698567, 18936166, 21990134, 17924331, 25085752, 22753008, 24312913, 23161852, 16267036, 28408614, 26689913, 15385441, 30287823, 30219179, 30617304, 33087888)
Ambry Genetics RCV000162967 SCV000213455 benign Hereditary cancer-predisposing syndrome 2014-11-18 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.
Laboratory for Molecular Medicine, Mass General Brigham Personalized Medicine RCV000159939 SCV000538455 uncertain significance not specified 2016-06-23 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: ClinVar: 3 B/LB, including expert panel
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000159939 SCV000699128 likely benign not specified 2023-06-22 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.427G>A (p.Glu143Lys) results in a conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8.4e-05 in 251024 control chromosomes. This frequency is not significantly higher than estimated for a pathogenic variant in BRCA1 causing Hereditary Breast And Ovarian Cancer Syndrome (8.4e-05 vs 0.001), allowing no conclusion about variant significance. c.427G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer. These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. The variant has been functionally evaluated and showed similar to wild-type activity in an HDR assay and intermediate activity in a less specific Single strand annealing (SSA) assay (Towler, 2013, Lu, 2015 and Starita, 2018). The HDR assay qualifies as a standardized gold-standard assay on the basis of the updated guidance provided by the ClinGen Sequence Variant Interpretation (SVI) Working Group (Brnich_2019). ClinGen SVI now recognizes benign functional evidence as sufficient for likely benign (Tavtigian_2018). Nine submitters have cited clinical-significance assessments for this variant to ClinVar after 2014 and classified as benign/likely benign (n=8) and VUS (n=1). Based on the evidence outlined above, the variant was classified as likely benign.
Counsyl RCV000031161 SCV000786473 benign Breast-ovarian cancer, familial, susceptibility to, 1 2018-05-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000159939 SCV000885069 likely benign not specified 2019-01-11 criteria provided, single submitter clinical testing
Color Diagnostics, LLC DBA Color Health RCV000162967 SCV000902846 likely benign Hereditary cancer-predisposing syndrome 2015-08-20 criteria provided, single submitter clinical testing
CHEO Genetics Diagnostic Laboratory, Children's Hospital of Eastern Ontario RCV001798032 SCV002043445 likely benign Breast and/or ovarian cancer 2022-07-20 criteria provided, single submitter clinical testing
Fulgent Genetics, Fulgent Genetics RCV002504841 SCV002796513 likely benign Familial cancer of breast; Breast-ovarian cancer, familial, susceptibility to, 1; Pancreatic cancer, susceptibility to, 4; Fanconi anemia, complementation group S 2022-03-10 criteria provided, single submitter clinical testing
Center for Genomic Medicine, Rigshospitalet, Copenhagen University Hospital RCV000159939 SCV004026818 benign not specified 2023-08-15 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031161 SCV000053761 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2010-11-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031161 SCV000145475 uncertain significance Breast-ovarian cancer, familial, susceptibility to, 1 2004-02-20 no assertion criteria provided clinical testing
Center for Precision Medicine, Meizhou People's Hospital RCV002250474 SCV002520914 uncertain significance Familial cancer of breast no assertion criteria provided literature only

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