ClinVar Miner

Submissions for variant NM_007299.4(BRCA1):c.199G>T (p.Asp67Tyr) (rs80357102)

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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) RCV000083176 SCV000244311 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 = 0.0000029
Invitae RCV000195312 SCV000075688 benign Hereditary breast and ovarian cancer syndrome 2018-01-06 criteria provided, single submitter clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000148404 SCV000190103 uncertain significance Breast and/or ovarian cancer 2014-06-01 criteria provided, single submitter research Low GERP score may suggest that this variant may belong in a lower pathogenicity class
GeneDx RCV000047675 SCV000209902 likely benign not specified 2017-08-28 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 RCV000162582 SCV000212998 benign Hereditary cancer-predisposing syndrome 2014-11-18 criteria provided, single submitter clinical testing
Counsyl RCV000083176 SCV000220787 likely benign Breast-ovarian cancer, familial 1 2014-10-13 criteria provided, single submitter literature only
CHEO Genetics Diagnostic Laboratory,Children's Hospital of Eastern Ontario RCV000195312 SCV000324827 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-08-27 criteria provided, single submitter clinical testing
Cancer Genetics and Genomics Laboratory,British Columbia Cancer Agency RCV000047675 SCV000586866 likely benign not specified 2017-04-18 criteria provided, single submitter clinical testing
Department of Pathology and Molecular Medicine,Queen's University RCV000047675 SCV000588027 benign not specified 2017-04-20 criteria provided, single submitter clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000047675 SCV000591248 benign not specified 2014-03-11 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589035 SCV000698905 benign not provided 2017-07-03 criteria provided, single submitter clinical testing Variant summary: This missense variant involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a pathogenic outcome. The variant is present at a low frequency in the control population (0.0076% in ExAC, 0.012% in European (Non-Finnish)), and has been reported in the literature in HBOC patients and families. Most of these publications, however, fail to provide co-segregation and co-occurrence data, and do not test for large deletions/insertions, and therefore do not provide strong evidence for the causality of this variant. In addition, one report, although a poster presentation, is provided by individuals from a reputable laboratory, Myriad, indicating the variant was found to co-occur with 9 pathogenic variants (gene and variants not specified) and was classified as benign. UMD lists variant in 15 individuals with classification of "1-Neutral". One of them carried a pathogenic BRCA2 variant c.1773_1776delTTAT (p.Ile591MetfsX22). Furthermore, several functional studies have been published and showed that the c.199G>T variant had a moderate effect on centrosome duplication (Kais_2012, Towler_2013), chromosomal instability, (Cochran_2015), and resulted in a moderate reduction in E3 ligase activity, but that the mutant protein had similar binding of BRCA1 to BARD1 (Caleca_2014, Ransburgh_2010, Morris_2006, Starita_2015) and wild-type levels of E2 interaction (Morris_2006). There was no difference in homologous recombination (Kais_2012, Ransburgh_2010), double strand break repair by the single-strand annealing pathway (Towler_2013), yeast colony size, spot formation, and yeast localization (Thouvenot_2016) between mutant BRCA1 with this variant and wild-type BRCA1. This variant also had no effect on splicing via patient cDNA and minigene splicing assay (Houdayer_2012, Thery_2011). Additionally, multifactorial probability based models showed a low odds in favor of causality (Lindor_2012, Easton_2007). In addition, multiple reputable databases, UMD, ARUP, and clincial labs classify the variant as "benign/likely benign, at-least 2 of whom have submitted/updated their submissions to ClinVar since the time of the previous classification of this variant in our laboratory." Therefore, taking all evidence into consideration, the variant of interest is classified as benign.
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000589035 SCV000883466 likely benign not provided 2017-08-24 criteria provided, single submitter clinical testing
Color RCV000162582 SCV000902756 likely benign Hereditary cancer-predisposing syndrome 2016-07-28 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083176 SCV000115250 uncertain significance Breast-ovarian cancer, familial 1 2007-03-07 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000083176 SCV000144627 uncertain significance Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing

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