ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4675G>A (p.Glu1559Lys) (rs80356988)

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Total submissions: 8
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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) RCV000031185 SCV001161548 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 = 0.99607
Ambry Genetics RCV000131823 SCV000186878 pathogenic Hereditary cancer-predisposing syndrome 2017-05-16 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Last nucleotide of exon,Other strong data supporting pathogenic classification,Functionally-validated splicing mutation,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031185 SCV000326020 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
GeneDx RCV000482921 SCV000564744 likely pathogenic not provided 2015-02-28 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4675G>A at the cDNA level. Using alternate nomenclature, this variant has been previously published as BRCA1 4794G>A. Located in last nucleotide of exon 14, multiple splicing models predict that this variant destroys the natural splice donor site for intron 14 and causes abnormal splicing. BRCA1 c.4675G>A has been reported in at least three individuals with ovarian cancer (Wappenschmidt 2012, Janavicius 2014, Tihomirova 2014). In addition, RNA analysis suggested that this variant results in partial loss of the natural splice donor site and activation of a cryptic splice donor site (Wappenschmidt 2012). Although the nucleotide substitution results in the change of a Glutamic Acid to a Lysine at codon 1559, and is called Glu1559Lys in the literature, we are using only the nucleotide nomenclature to refer to the mutation since the defect is mainly due to abnormal splicing rather than a resulting missense pathogenic variant. BRCA1 c.4675G>A 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. The nucleotide which is altered, a guanine (G) at base 4675, is conserved across species. Based on the current evidence, we consider this mutation to be a likely pathogenic variant.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000482921 SCV001133595 pathogenic not provided 2019-02-11 criteria provided, single submitter clinical testing The best available variant frequency is uninformative. Statistically enriched in patients. Predicted to have a tolerated effect on the protein. One other pathogenic or likely pathogenic variant affects the same amino acid. Predicted to negatively affect a known splice site. Assessment of experimental evidence suggests this variant results in abnormal protein function.
Sharing Clinical Reports Project (SCRP) RCV000031185 SCV000053785 pathogenic Breast-ovarian cancer, familial 1 2012-05-01 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031185 SCV000145148 pathogenic Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Research Molecular Genetics Laboratory,Women's College Hospital, University of Toronto RCV000496604 SCV000587416 pathogenic Hereditary breast and ovarian cancer syndrome 2014-01-31 no assertion criteria provided research

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