ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.140G>A (p.Cys47Tyr) (rs80357150)

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Total submissions: 4
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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
Integrated Genetics/Laboratory Corporation of America 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 RCV000775194 SCV000909420 likely pathogenic Hereditary cancer-predisposing syndrome 2018-06-12 criteria provided, single submitter clinical testing

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