ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.131G>A (p.Cys44Tyr) (rs80357446)

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Total submissions: 9
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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) RCV000077486 SCV000244299 pathogenic 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 5 based on posterior probability = 1
GeneDx RCV000235119 SCV000209888 pathogenic not provided 2018-06-05 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.131G>A at the cDNA level, p.Cys44Tyr (C44Y) at the protein level, and results in the change of a Cysteine to a Tyrosine (TGC>TAC). Using alternative nomenclature, this variant would be defined as BRCA1 250G>A. BRCA1 Cys44Tyr impacts protein function with respect to reduced cellular proliferation, nuclear localization, and E3 ubiquitin ligase activity, as well as an inability to form a functional heterodimer with BARD1 (Brzovic 2003, Morris 2006, Millot 2011, Starita 2015). In addition, colony size, spot formation, and yeast localization assays of this variant also demonstrated a pathogenic effect (Thouvenot 2016). BRCA1 Cys44Tyr has been observed in at least two individuals with breast cancer, including one woman with early-onset, triple negative disease and family history of bilateral breast cancer (Sweet 2010, Sun 2017). Sweet et al. (2010) predicted BRCA1 Cys44Tyr to be likely deleterious using a multifactorial model that incorporated evolutionary conservation, age at diagnosis, tumor grade and hormone receptor status. Using these data as the prior probability, another multifactorial model by Lindor et al. (2012) also strongly predicted this variant to be deleterious. BRCA1 Cys44Tyr was not observed in large population cohorts (Lek 2016). This variant is located in the RING finger domain, within the Ub site, and in the region of interaction with BARD1 and BRD7 (Wu 1996, Narod 2004, Harte 2010, Paul 2014). In silico analysis, which includes protein predictors and evolutionary conservation, supports a deleterious effect. Based on currently available evidence, we consider this variant to be pathogenic.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000077486 SCV000325011 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Counsyl RCV000077486 SCV000489328 pathogenic Breast-ovarian cancer, familial 1 2016-09-21 criteria provided, single submitter clinical testing
Ambry Genetics RCV000509871 SCV000607781 pathogenic Hereditary cancer-predisposing syndrome 2019-04-16 criteria provided, single submitter clinical testing In silico models in agreement (deleterious) and/or completely conserved position in appropriate species;Deficient protein function in appropriate functional assay(s);Well-characterized mutation at same position;Structural Evidence;Rarity in general population databases (dbsnp, esp, 1000 genomes)
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000235119 SCV001133482 pathogenic not provided 2019-01-07 criteria provided, single submitter clinical testing Not found in the total gnomAD dataset, and the data is high quality (0/282214 chr). Predicted to have a damaging effect on the protein. Located in potentially important domain of the protein. Two other pathogenic variants affect the same amino acid. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Sharing Clinical Reports Project (SCRP) RCV000077486 SCV000109284 pathogenic Breast-ovarian cancer, familial 1 2008-07-24 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000077486 SCV000144403 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000077486 SCV001242870 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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