ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4675G>C (p.Glu1559Gln) (rs80356988)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131825 SCV000186880 pathogenic Hereditary cancer-predisposing syndrome 2020-07-05 criteria provided, single submitter clinical testing The c.4675G>C variant (also known as p.E1559Q) is located in coding exon 13 of the BRCA1 gene. This variant results from a G to C substitution at nucleotide position 4675. The glutamic acid at codon 1559 is replaced by glutamine, an amino acid with highly similar properties. However, this change occurs in the last base pair of coding exon 13 which makes it likely to have some effect on normal mRNA splicing. This alteration is predicted to decrease the efficiency of the native splice donor site by the BDGP and ESEfinder in silico models. RNA analysis showed that this alteration induces expression of a transcript lacking 11 nucleotides at the end of coding exon 13 (also called exon 15 in the literature-Davy G et al. Eur. J. Hum. Genet., 2017 10;25:1147-1154). Furthermore, a close match alteration at the same nucleotide position, BRCA1 c.4675G>A has been shown in multiple studies to have the same splice defect as this alteration (Wappenschmidt B et al. PLoS ONE, 2012 Dec; Wangensteen T et al. Hered Cancer Clin Pract, 2019 May;17:14; Koczkowska M et al. Cancers (Basel), 2018 Nov;10: ). This alteration was functional in a protein assay (Woods NT et al. NPJ Genom Med, 2016 Mar;1) and is predicted to be tolerated by in silico analysis. Based on the supporting evidence, this alteration is interpreted as a disease-causing mutation.
Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), c/o University of Cambridge RCV000031186 SCV000326021 pathogenic Breast-ovarian cancer, familial 1 2015-10-02 criteria provided, single submitter clinical testing
Color Health, Inc RCV000131825 SCV001340175 likely pathogenic Hereditary cancer-predisposing syndrome 2020-05-01 criteria provided, single submitter clinical testing
Invitae RCV001379224 SCV001576985 likely pathogenic Hereditary breast and ovarian cancer syndrome 2020-06-28 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 1559 of the BRCA1 protein (p.Glu1559Gln). The glutamic acid residue is moderately conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant also falls at the last nucleotide of exon 14 of the BRCA1 coding sequence, which is part of the consensus splice site for this exon. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with clinical features and/or family history of hereditary breast and/or ovarian cancer (PMID: 28975465, 29446198). ClinVar contains an entry for this variant (Variation ID: 37605). Algorithms developed to predict the effect of missense changes on protein structure and function (SIFT, PolyPhen-2, Align-GVGD) all suggest that this variant is likely to be tolerated, but these predictions have not been confirmed by published functional studies and their clinical significance is uncertain. Nucleotide substitutions within the consensus splice site are a relatively common cause of aberrant splicing (PMID: 17576681, 9536098). Experimental studies have shown that this variant disrupts mRNA splicing (PMID: 28905878). This variant disrupts the c.4675 nucleotide in the BRCA1 gene. Other variant(s) that disrupt this nucleotide have been determined to be pathogenic (PMID: 23239986, 25066507, 24333842, 23239986, 31143303). This suggests that this nucleotide is clinically significant, and that variants that disrupt this position are likely to be disease-causing. 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.
Sharing Clinical Reports Project (SCRP) RCV000031186 SCV000053786 likely pathogenic Breast-ovarian cancer, familial 1 2012-09-13 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000031186 SCV000145149 pathogenic Breast-ovarian cancer, familial 1 2002-05-29 no assertion criteria provided clinical testing
Laboratoire de Biologie et Génétique du Cancer,Centre François Baclesse RCV000031186 SCV000538190 pathogenic Breast-ovarian cancer, familial 1 no assertion criteria provided clinical testing

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.