ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.5506G>A (p.Glu1836Lys) (rs80356942)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000195397 SCV000077037 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-13 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 disease. ClinVar contains an entry for this variant (Variation ID: 55605). Experimental studies suggest that this missense change exhibits a temperature-sensitive behavior with lower transcriptional activity at 37°C in mammalian cell lines (PMID: 24845084), and may have reduced peptide binding activity (PMID: 20516115, 21473589). 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 2016-08-03 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
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

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