ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.130T>A (p.Cys44Ser) (rs80357327)

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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) RCV000111838 SCV000244298 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
Ambry Genetics RCV000222092 SCV000277476 pathogenic Hereditary cancer-predisposing syndrome 2015-08-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000111838 SCV000296457 pathogenic Breast-ovarian cancer, familial 1 2016-04-23 criteria provided, single submitter clinical testing
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000111838 SCV000325009 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000444956 SCV000516958 pathogenic not provided 2015-05-08 criteria provided, single submitter clinical testing This pathogenic variant is denoted BRCA1 c.130T>A at the cDNA level, p.Cys44Ser (C44S) at the protein level, and results in the change of a Cysteine to a Serine (TGC>AGC). This variant, also published as BRCA1 249T>A using alternate nomenclature, has been reported in women with a history of breast and/or ovarian cancer and has been reported to be a Greenlandic founder pathogenic variant (Borg 2010, Hansen 2010, Karami 2013). The mutation was strongly predicted by Lindor et al. (2012) to be deleterious based on tumor pathology, clinical histories, family studies and co-occurrence with deleterious variants. BRCA1 Cys44Ser was not observed in approximately 6,500 individuals of European and African American ancestry in the NHLBI Exome Sequencing Project, indicating it is not a common benign variant in these populations. Since Cysteine and Serine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Cys44Ser occurs at a position that is conserved across species and is located within the RING-type Zinc finger domain and region of interaction with BARD1 (Narod 2004, Roy 2012, Uniprot). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on the current evidence, we consider this variant to be pathogenic.
Department of Medical Genetics,Oslo University Hospital RCV000111838 SCV000564369 pathogenic Breast-ovarian cancer, familial 1 2015-07-22 criteria provided, single submitter clinical testing
Counsyl RCV000111838 SCV000677631 pathogenic Breast-ovarian cancer, familial 1 2016-12-13 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000589017 SCV000698845 pathogenic Hereditary breast and ovarian cancer syndrome 2017-06-09 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.130T>A (p.Cys44Ser) variant involves the alteration of a conserved nucleotide, resulting in a missense substitution at a highly conserved cysteine residue in the RING finger domain (InterPro). 5/5 in silico tools predict a damaging outcome for this variant. This variant is absent from the large control database ExAC and control cohorts reported in the literature (0/112062 control chromosomes). The variant has been identified in numerous HBOC patient. Several overlapping variants are present in HGMD (Cys44Arg, Cys44Gly, Cys44Phe, and Cys44Tyr), suggesting a mutational hotspot that is critical for protein function. In addition, this variant C44S has been functionally tested and shown to disrupt BARD1 binding, and impairs ubiquitin ligase activity and homolgy-directed repair (Starita_2015). Multiple clinical diagnostic laboratories/reputable databases have classified this variant as pathogenic. Taken together, this variant is classified as pathogenic.
Breast Cancer Information Core (BIC) (BRCA1) RCV000111838 SCV000144397 uncertain significance Breast-ovarian cancer, familial 1 2003-12-23 no assertion criteria provided clinical testing

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