ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.3868A>G (p.Lys1290Glu) (rs80357254)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 10
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000759529 SCV000210160 uncertain significance not provided 2018-07-19 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3868A>G at the cDNA level, p.Lys1290Glu (K1290E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAA>GAA). Using alternate nomenclature, this variant would be defined as BRCA1 3987A>G. This variant was observed in several individuals with a personal and/or family history of breast and/or ovarian cancer (Minucci 2015, Azzollini 2016, Alemar 2017). BRCA1 Lys1290Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the SCD domain and a region known to interact with multiple other proteins (Narod 2004, Clark 2012, Paul 2014). 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 Lys1290Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000218431 SCV000274418 uncertain significance Hereditary cancer-predisposing syndrome 2018-06-27 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV000234532 SCV000289789 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-12-26 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 1290 of the BRCA1 protein (p.Lys1290Glu). The lysine residue is weakly conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is present in population databases (rs80357254, ExAC 0.001%). This variant has been observed in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 26306726, 29161300, 27062684). ClinVar contains an entry for this variant (Variation ID: 91617). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. These predictions have not been confirmed by published functional studies and their clinical significance is uncertain. 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.
Counsyl RCV000077134 SCV000785413 uncertain significance Breast-ovarian cancer, familial 1 2017-07-25 criteria provided, single submitter clinical testing
Mendelics RCV000234532 SCV000839245 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000759529 SCV000888903 uncertain significance not provided 2018-01-19 criteria provided, single submitter clinical testing
Mendelics RCV000077134 SCV001140540 uncertain significance Breast-ovarian cancer, familial 1 2019-05-28 criteria provided, single submitter clinical testing
Color RCV000218431 SCV001345620 uncertain significance Hereditary cancer-predisposing syndrome 2019-08-22 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV001193691 SCV001362703 uncertain significance not specified 2019-04-22 criteria provided, single submitter clinical testing Variant summary: BRCA1 c.3868A>G (p.Lys1290Glu) results in a conservative amino acid change in the encoded protein sequence. Five of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 251164 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.3868A>G has been reported in the literature in individuals affected with Breast and Ovarian Cancer (Alemar_2017, Azzollini_2016, Minucci_2015). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 exon 20 del (Minucci_2015)), providing supporting evidence for a benign role. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000077134 SCV000108931 uncertain significance Breast-ovarian cancer, familial 1 2012-09-07 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.