ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2884G>A (p.Glu962Lys) (rs80356955)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000111956 SCV001161497 benign 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 1 based on posterior probability = 0.000971
Invitae RCV000195390 SCV000076013 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-04 criteria provided, single submitter clinical testing
GeneDx RCV000048000 SCV000210137 uncertain significance not provided 2018-11-06 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.2884G>A at the cDNA level, p.Glu962Lys (E962K) at the protein level, and results in the change of a Glutamic Acid to a Lysine (GAA>AAA). This variant, also known as BRCA1 3003G>A using alternate nomenclature, has been observed in a woman with a history of unilateral breast cancer (Borg 2010). An in vitro-based homology-directed repair (HDR) assay showed this variant to exhibit HDR activity comparable to wildtype (Lu 2015). BRCA1 Glu962Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located within the DNA and RAD51 binding domains (Chen 1998, Narod 2004). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA1 Glu962Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000213861 SCV000272974 uncertain significance Hereditary cancer-predisposing syndrome 2020-01-15 criteria provided, single submitter clinical testing The p.E962K variant (also known as c.2884G>A), located in coding exon 9 of the BRCA1 gene, results from a G to A substitution at nucleotide position 2884. The glutamic acid at codon 962 is replaced by lysine, an amino acid with similar properties. This alteration was reported in a cohort of 55630 patients who underwent BRCA1 gene sequencing at a commercial laboratory and was classified as a variant of unknown significance (Judkins T et al. Cancer Res., 2005 Nov;65:10096-103).​ <span style="background-color:initial">This alteration was observed in 0/705 women with contralateral breast cancer and 1/1398 women with unilateral breast cancer, and was considered to be a variant of uncertain significance (Borg A et al. Hum. Mutat. 2010 Mar;31:E1200-40). Functional analysis of p.E926K has demonstrated in vitro HDR activity comparable to wild type protein (Lu C et al. Nat Commun. 2015 Dec 22;6:10086). In one study, this alteration was seen in 1 of 7400 Czech high risk breast and/or ovarian cancer families (Machackova E et al. Klin Onkol, 2019;32:51-71). This amino acid position is not well conserved in available vertebrate species. In addition, this alteration is predicted to be tolerated by in silico analysis. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000048000 SCV000888875 uncertain significance not provided 2019-10-31 criteria provided, single submitter clinical testing
Color Health, Inc RCV000213861 SCV000903258 benign Hereditary cancer-predisposing syndrome 2016-03-30 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000779888 SCV000916775 uncertain significance not specified 2017-12-28 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2884G>A (p.Glu962Lys) variant involves the alteration of a non-conserved nucleotide, that results in the substitution of a glutamine amino acid for lysine in the DNA binding domain of the BRCA1 protein (Lu 2015). Since a lysine amino acid residue is found in multiple mammalian species at this position, this suggests that the variant of interest might not adversely affect protein function. 3/5 in silico tools predict a benign outcome for this variant. Moreover, in a functional study the variant protein was found to have a similar homology-directed repair (HDR) activity to the wild type protein (Lu 2015). This variant was found in 4/277044 control chromosomes at a frequency of 0.0000144, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA1 variant (0.0010005). Though the variant has been reported in HBOC patients (Judkins 2005, Borg 2010), no convincing evidence was provided for causality. This variant has been reported in five patients in the UMD database, however a pathogenic BRCA2 variant (c.145G>T (p.Glu49X)) was also present in one of the patients, suggesting that the variant of interest was not the primary cause of disease in this patient. Though multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance, considering all the available evidence, this variant is classified as VUS possibly benign.
Research and Development, ARUP Laboratories RCV001661969 SCV001878274 benign Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Breast Cancer Information Core (BIC) (BRCA1) RCV000111956 SCV000144570 uncertain significance Breast-ovarian cancer, familial 1 2004-02-20 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.