ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.140G>A (p.Cys47Tyr) (rs80357150)

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Total submissions: 7
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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) RCV000258496 SCV001161536 pathogenic Breast-ovarian cancer, familial 1 2019-06-18 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
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000258496 SCV000325064 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000590698 SCV000698863 pathogenic Hereditary breast and ovarian cancer syndrome 2019-11-20 criteria provided, single submitter clinical testing Variant Summary: BRCA1 c.140G>A (p.Cys47Tyr) results in a non-conservative amino acid change located in the Zinc finger, RING-type domain (IPR001841) of the encoded protein sequence, and has been implicated to "likely to result in a defective protein, as this cysteine residue is a major constituent of the BRCA1 ring finger" (Ithier_1996). Five of five in-silico tools predict a damaging effect of the variant on protein function with multiple publications citing the variant as "disease-causing," although with limited information, predominantly based on in silico programs (example, Martelotto_2014). The variant was absent in 249656 control chromosomes (gnomAD). The variant, c.140G>A, has been reported in the literature in multiple individuals affected with breast and/or ovarian cancer (Ithier_1996, Hondow_2011, Golmard _2017, Rebbeck_2018) and the UMD database cites the variant in 31 individuals with a classification of "Causal," with no additional information for an independent evaluation. These data indicate that the variant is very likely to be associated with disease. Two ClinVar submitters (evaluation after 2014) cite the variant as likely pathogenic/pathogenic. Based on the evidence outlined above, the variant was re-classified as pathogenic.
Color Health, Inc RCV000775194 SCV000909420 likely pathogenic Hereditary cancer-predisposing syndrome 2019-06-19 criteria provided, single submitter clinical testing
Invitae RCV000590698 SCV001574883 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-09-17 criteria provided, single submitter clinical testing This sequence change replaces cysteine with tyrosine at codon 47 of the BRCA1 protein (p.Cys47Tyr). 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 (ExAC no frequency). This variant has been reported in the literature in many individuals affected with possible hereditary breast and/or ovarian cancer (PMID: 12360411, 29446198, 11118466, 17826769, 9150149, 22762150). ClinVar contains an entry for this variant (Variation ID: 54246). This variant affects the highly conserved Cys47 residue within the N-terminal RING domain of the BRCA1 protein (PMID: 22843421). Based on a multifactorial likelihood algorithm using genetic and statistical data, this variant has been determined to have a high probability of being pathogenic (PMID: 31131967). Experimental studies have shown that this variant affects BRCA1 protein function (PMID: 25823446, 30209399). In summary, the currently available evidence indicates that the variant is pathogenic, but additional data are needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.
Brotman Baty Institute,University of Washington RCV000258496 SCV001242937 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000258496 SCV001550843 likely pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing The BRCA1 p.Cys47Tyr variant was identified in 5 of 6610 proband chromosomes (frequency: 0.0008) from individuals or families with breast and/or ovarian cancer (Gad 2002, Golmard 2017, Lai 2015, Stoppa-Lyonnet 1997, Thompson 2002); however, control chromosomes were not evaluated in these studies, thus the prevalence of this variant in the general population could not be determined. The variant was also identified in the following databases: dbSNP (ID: rs80357150) as “With Pathogenic, other allele,” ClinVar (1x pathogenic, Consortium of Investigators of Modifiers of BRCA1/2 CIMBA), Clinvitae (1x pathogenic), and UMD-LSDB (31x, causal). The variant was not identified in Cosmic, MutDB, LOVD 3.0, BIC Database, ARUP Laboratories, or the Zhejiang Colon Cancer Database. The variant was not identified in the control databases: the 1000 Genomes Project, the NHLBI GO Exome Sequencing Project, the Exome Aggregation Consortium (August 8th 2016), or the Genome Aggregation Database (Feb 27, 2017). The p.Cys47 residue is located in the Zinc RING finger domain of the BRCA1 protein, a domain known to bind to BARD1 and BAP1 (Thompson 2002). This increases the likelihood that this is a pathogenic variant. The p.Cys47 residue is conserved across mammals and other organisms, and computational analyses (PolyPhen-2, SIFT, AlignGVGD, BLOSUM, MutationTaster) suggest that the variant may impact the protein; however, this information is not predictive enough to assume pathogenicity. The variant occurs outside of the splicing consensus sequence and in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer, HumanSpliceFinder) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time although we would lean towards a more pathogenic role for this variant. This variant is classified as likely pathogenic.

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