ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.3619A>G (p.Lys1207Glu) (rs80357455)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000074582 SCV000108667 uncertain significance not provided 2018-02-13 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.3619A>G at the cDNA level, p.Lys1207Glu (K1207E) at the protein level, and results in the change of a Lysine to a Glutamic Acid (AAG>GAG). Using alternate nomenclature, this variant would be defined as BRCA1 3738A>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Lys1207Glu was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Lys1207Glu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000195893 SCV000254978 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-04 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 1207 of the BRCA1 protein (p.Lys1207Glu). The lysine residue is moderately conserved and there is a small physicochemical difference between lysine and glutamic acid. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA1-related disease. ClinVar contains an entry for this variant (Variation ID: 89060). 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.

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