ClinVar Miner

Submissions for variant NM_007294.3(BRCA1):c.4186C>A (p.Gln1396Lys) (rs80357011)

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Total submissions: 2
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000159988 SCV000210171 uncertain significance not provided 2018-02-12 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.4186C>A at the cDNA level, p.Gln1396Lys (Q1396K) at the protein level, and results in the change of a Glutamine to a Lysine (CAG>AAG). Using alternate nomenclature, this variant would be defined as BRCA1 4305C>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Gln1396Lys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is located in the SCD domain and in a region known to interact with multiple proteins (Chen 1998, Narod 2004, Clark 2012). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available information, it is unclear whether BRCA1 Gln1396Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000466202 SCV000549259 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-12-09 criteria provided, single submitter clinical testing This sequence change replaces glutamine with lysine at codon 1396 of the BRCA1 protein (p.Gln1396Lys). The glutamine residue is highly conserved and there is a small physicochemical difference between glutamine and lysine. This variant is not present in population databases (ExAC no frequency) and has not been reported in the literature in individuals with a BRCA1-related disease. This variant is also known as c.4305C>A. Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Deleterious"; PolyPhen-2: "Benign"; Align-GVGD: "Class C45"). In summary, this variant is a novel missense change with uncertain impact on protein function. It has been classified as a Variant of Uncertain Significance.

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