ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.1747A>G (p.Lys583Glu) (rs80356928)

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Total submissions: 6
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000131990 SCV000187048 uncertain significance Hereditary cancer-predisposing syndrome 2016-12-02 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence,In silico models in agreement (benign)
Invitae RCV000168342 SCV000219031 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-28 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 583 of the BRCA1 protein (p.Lys583Glu). 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 (rs80356928, ExAC 0.03%). This variant has been reported in the literature in an individual with breast cancer (PMID: 8531968). This variant is also known as 1606A>G (K536E) in the literature. ClinVar contains an entry for this variant (Variation ID: 91562). 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.
GeneDx RCV000485566 SCV000568918 uncertain significance not provided 2017-08-29 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.1747A>G at the cDNA level, p.Lys583Glu (K583E) 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 1866A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Lys583Glu was observed at an allele frequency of 0.03% (3/10,324) in individuals of African ancestry in large population cohorts (NHLBI Exome Sequencing Project, The 1000 Genomes Consortium 2015, Lek 2016). Since Lysine and Glutamic Acid differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA1 Lys583Glu occurs at a position that is not conserved and is located within the DNA binding domain and regions of interaction with RAD50 and STAT1 (Zhong 1999, Ouchi 2000, Narod 2004). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available evidence, it is unclear whether BRCA1 Lys583Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Color RCV000131990 SCV000906664 likely benign Hereditary cancer-predisposing syndrome 2016-11-14 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000485566 SCV001133497 uncertain significance not provided 2019-03-05 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000077079 SCV000108876 uncertain significance Breast-ovarian cancer, familial 1 2007-05-31 no assertion criteria provided clinical testing

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