ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.4186C>A (p.Gln1396Lys)

gnomAD frequency: 0.00001  dbSNP: rs80357011
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Total submissions: 3
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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 ovarian cancer syndrome 2023-10-27 criteria provided, single submitter clinical testing This sequence change replaces glutamine, which is neutral and polar, with lysine, which is basic and polar, at codon 1396 of the BRCA1 protein (p.Gln1396Lys). This variant is present in population databases (rs80357011, gnomAD 0.01%). This variant has not been reported in the literature in individuals affected with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 182160). An algorithm developed to predict the effect of missense changes on protein structure and function (PolyPhen-2) suggests that this variant is likely to be tolerated. 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.
Ambry Genetics RCV001022002 SCV001183689 uncertain significance Hereditary cancer-predisposing syndrome 2023-05-26 criteria provided, single submitter clinical testing The p.Q1396K variant (also known as c.4186C>A), located in coding exon 11 of the BRCA1 gene, results from a C to A substitution at nucleotide position 4186. This variant impacts the first base pair of coding exon 11. The glutamine at codon 1396 is replaced by lysine, an amino acid with similar properties. This alteration was identified in an individual diagnosed with ovarian cancer (Kadri MSN et al. Front Oncol, 2020 Jan;10:568786). This amino acid position is highly conserved in available vertebrate species. In addition, the in silico prediction for this alteration is inconclusive. Since supporting evidence is limited at this time, the clinical significance of this alteration remains unclear.

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