ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.427G>A (p.Glu143Lys) (rs80356991)

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Total submissions: 11
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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 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 RCV000048510 SCV000076523 likely benign Hereditary breast and ovarian cancer syndrome 2017-12-21 criteria provided, single submitter clinical testing
GeneDx RCV000159939 SCV000210075 likely benign not specified 2017-12-06 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 RCV000162967 SCV000213455 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
Laboratory for Molecular Medicine,Partners HealthCare 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
Integrated Genetics/Laboratory Corporation of America RCV000159939 SCV000699128 likely benign not specified 2019-01-07 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 8e-05 in 276560 control chromosomes. This frequency is not significantly higher than expected for a pathogenic variant in BRCA1 causing Hereditary Breast and Ovarian Cancer (8e-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 report(s) 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). In addition, this variant has been reported as "1 - Not pathogenic or of no clinical significance" based on posterior probability calculation being 0.000, which combines prior probabilities of causality derived from an evolutionary sequence conservation model and likelihoods of causality derived from measures of associations between the VUS and cancer (FH, segregation, co-occurrence with deleterious variants, and histopathology data; see references Lindor_2012 and Easton_2007). Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation (4x likely benign and 1x VUS). Our laboratory has classified this variant as a "VUS-possibly normal" in a series of conservative re-evaluations spanning three years (2015-2018), however, no new evidence supporting pathogenicity have been reported and at-least four other testing laboratories have classified this variant as benign/likely benign since our original classification. Therefore, the overall evidence seems to be shifting from uncertain significance to likely benign consistent with at-least three independent reports (spanning 2013-2018) demonstrating no effect on homology directed repair activity (HDR). Based on the evidence outlined above, until more clinical and prevalence data become available, the variant was classified as likely benign.
Counsyl RCV000031161 SCV000786473 benign Breast-ovarian cancer, familial 1 2018-05-14 criteria provided, single submitter clinical testing
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000588563 SCV000885069 uncertain significance not provided 2017-09-14 criteria provided, single submitter clinical testing The BRCA1 c.427G>A, p.Glu143Lys variant has been reported in patients with breast and/or ovarian cancer (Easton 2007, Lindor 2012). Multi-factorial analysis (based on co-occurrence, tumor pathology, co-segregation and family history) has indicated that the variant has low probability of causation or pathogenicity (Easton 2007, Lindor 2012). The variant is listed in the ClinVar database (Variation ID: 37580), in the dbSNP variant database (rs80356991), and observed at a frequency of 0.007955 percent (22/276560 alleles) in the Genome Aggregation Database, a general population database. The glutamate at residue 143 is moderately conserved, and computational algorithms (Align GV/GD, Mutation Taster, PolyPhen-2) predict that the variant has no impact on the protein. Due to the limited information regarding this variant, its clinical significance could not be determined with certainty, though the available evidence suggests a low likelihood of causing disease. References: Easton D et al. A systematic genetic assessment of 1,433 sequence variants of unknown clinical significance in the BRCA1 and BRCA2 breast cancer-predisposition genes. Am J Hum Genet. 2007 81(5):873-83. Lindor N et al. A review of a multifactorial probability-based model for classification of BRCA1 and BRCA2 variants of uncertain significance (VUS). Hum Mutat. 2012 33(1):8-21.
Color RCV000162967 SCV000902846 likely benign Hereditary cancer-predisposing syndrome 2015-08-20 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031161 SCV000053761 uncertain significance Breast-ovarian cancer, familial 1 2010-11-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031161 SCV000145475 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 no assertion criteria provided clinical testing

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