ClinVar Miner

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

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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) 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 The p.C44Y variant (also known as c.131G>A), located in coding exon 2 of the BRCA1 gene, results from a G to A substitution at nucleotide position 131. The cysteine at codon 44 is replaced by tyrosine, an amino acid with highly dissimilar properties. This alteration, along with another alteration, p.C44S, at the same position, has been classified as definitely pathogenic (p>0.99) by multifactorial analysis, which integrates the following lines of evidence to produce a quantitative likelihood of pathogenicity: in silico prediction models, segregation with disease, tumor characteristics, mutation co-occurrence (Easton D et al. Am J Hum Genet. 2007;81:873-883; Vallee M et al. Hum Mutat. 2012 Jan;33(1):22-8; Lindor NM et al. Hum. Mutat., 2012 Jan;33:8-21). This alteration was shown to disrupt the function of the protein in multiple functional studies using different assays (Millot GA et al. Hum. Mutat., 2011 Dec;32:1470-80; Starita LM et al. Genetics, 2015 Jun;200:413-22; Thouvenot P et al. PLoS Genet., 2016 Jun;12:e1006096). In addition, a recent study found that this nucleotide substitution is deleterious in a high throughput genome editing haploid cell survival assay (Findlay GM et al. Nature. 2018 10;562(7726):217-222). This amino acid position is highly conserved in available vertebrate species. In addition, this alteration is predicted to be possibly damaging and deleterious by PolyPhen and SIFT in silico analyses, respectively.Based on the majority of available evidence, this alteration is classified as a disease-causing mutation.
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.
Invitae RCV001386839 SCV001587208 pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-23 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 44 of the BRCA1 protein (p.Cys44Tyr). The cysteine residue is highly conserved and there is a large physicochemical difference between cysteine and tyrosine. This variant is not present in population databases (rs80357446, ExAC no frequency). This variant has been reported in families affected with breast and ovarian cancer (PMID: 19543972, 27083775). ClinVar contains an entry for this variant (Variation ID: 54199). Based on a multifactorial likelihood algorithm using genetic, in silico, and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 19543972, 21990134). Experimental studies in yeast cells have shown that this missense change results in increased cell proliferation and sub-cellular mislocalization of the BRCA1 protein (PMID: 21922593, 27272900). A different missense substitution at this codon (p.Cys44Phe) has been determined to be pathogenic (PMID: 19543972, 21990134, 27272900). This suggests that the cysteine residue is critical for BRCA1 protein function and that other missense substitutions at this position may also be pathogenic. For these reasons, this variant has been classified as Pathogenic.
Research and Development, ARUP Laboratories RCV001660054 SCV001878105 pathogenic Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
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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