ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.5506G>A (p.Glu1836Lys) (rs80356942)

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
Invitae RCV000195397 SCV000077037 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-10-21 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with lysine at codon 1836 of the BRCA1 protein (p.Glu1836Lys). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and lysine. This variant is present in population databases (rs80356942, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 55605). Experimental studies are conflicting or provide insufficient evidence to determine the effect of this variant on BRCA1 protein function (PMID: 24845084, 20516115, 21473589, 20516115, 30209399, 30765603). Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional studies. In summary, the available evidence is currently insufficient to determine the role of this variant in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
GeneDx RCV000168525 SCV000210229 uncertain significance not provided 2015-10-23 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.5506G>A at the cDNA level, p.Glu1836Lys (E1836K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAG>AAG). Using alternate nomenclature, this variant would be defined as BRCA1 5625G>A. Functional assays interrogating this variant have found discrepant results. While in vitro assays by Lee et al. (2010) found that BRCA1 Glu1836Lys resulted in decreased binding activity and specificity to a phosphopeptide target, Coquelle et al. (2011) reported that this variant did not cause a dramatic reduction in phosphopeptide binding. Assays interrogating transcriptional activity have also been discrepant, with Lee et al. finding an uncertain level of activity and Carvalho et al. (2014) reporting decreased transactivation. Finally, Lee et al. also found that BRCA1 Glu1836Lys was not protease sensitive, indicating that this variant does not cause abnormal protein folding. BRCA1 Glu1836Lys 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 Glutamic Acid and Lysine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Glu1836Lys occurs at a position that is conserved in mammals and is located in the BRCT2 domain (Paul 2014, UniProt). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information, it is unclear whether BRCA1 Glu1836Lys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000219922 SCV000276176 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-21 criteria provided, single submitter clinical testing The p.E1836K variant (also known as c.5506G>A and 5625G>A), located in coding exon 22 of the BRCA1 gene, results from a G to A substitution at nucleotide position 5506. The glutamic acid at codon 1836 is replaced by lysine, an amino acid with similar properties. This alteration is located in the BRCT domain of BRCA1. One study, which assessed the effect of BRCT missense alterations by structure and sequence based computational analysis, found this alteration to have a probability of affecting structure and function of 0.48 and 0.42, using two sets of analytic features. Additionally, refined sequence based analysis predicted this alteration to affect function (Williams RS et al. J. Biol. Chem. 2003 Dec; 278(52):53007-16). Using several different structural and functional assays, another study found this alteration to be structurally stable; however, they did predict compromised binding activity and specificity, with less than 10% of wild type for both parameters, and found transcriptional activation to be at 55% of wild type, resulting in a classification of uncertain significance for this alteration (Lee MS et al. Cancer Res. 2010 Jun; 70(12):4880-90). Additionally, while one study suggested that this alteration could perturb phosphopeptide recognition and binding (Campbell SJ et al. Structure 2010 Feb; 18(2):167-76), another study showed that this alteration does not dramatically affect this function (Coquelle N et al. Biochemistry 2011 May; 50(21):4579-89). This amino acid position is well conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is conflicting at this time, the clinical significance of this alteration remains unclear.
Color Health, Inc RCV000219922 SCV001352261 uncertain significance Hereditary cancer-predisposing syndrome 2020-04-28 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA1) RCV000112686 SCV000145554 uncertain significance Breast-ovarian cancer, familial 1 2004-11-25 no assertion criteria provided clinical testing
Foulkes Cancer Genetics LDI, Lady Davis Institute for Medical Research RCV000735480 SCV000863617 likely benign Breast and/or ovarian cancer 2013-06-20 no assertion criteria provided clinical testing
Brotman Baty Institute,University of Washington RCV000112686 SCV001242060 not provided Breast-ovarian cancer, familial 1 no assertion provided in vitro

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.