ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3868A>G (p.Lys1290Glu) (rs80357254)

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Total submissions: 7
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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 2015-03-10 criteria provided, single submitter clinical testing
Invitae RCV000234532 SCV000289789 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-01-28 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%) but has not been reported in the literature in individuals with a BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 91617). The glutamic acid amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. In addition, 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. In summary, this is a rare missense change that is not predicted to affect protein function or cause disease. However, the evidence is insufficient at this time to prove that conclusively. 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
Sharing Clinical Reports Project (SCRP) RCV000077134 SCV000108931 uncertain significance Breast-ovarian cancer, familial 1 2012-09-07 no assertion criteria provided clinical testing

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