ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.339C>G (p.Asn113Lys) (rs587779367)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
GeneDx RCV000074580 SCV000108665 uncertain significance not provided 2017-11-27 criteria provided, single submitter clinical testing This variant is denoted BRCA1 c.339C>G at the cDNA level, p.Asn113Lys (N113K) at the protein level, and results in the change of an Asparagine to a Lysine (AAC>AAG). Using alternate nomenclature, this variant would be defined as BRCA1 458C>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA1 Asn113Lys was not observed in large population cohorts (Lek 2016). Since Asparagine and Lysine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA1 Asn113Lys is located in the BRD7 binding domain (Harte 2010). In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA1 Asn113Lys is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000564284 SCV000665839 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-23 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Invitae RCV001043000 SCV001206710 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-09-25 criteria provided, single submitter clinical testing This sequence change replaces asparagine with lysine at codon 113 of the BRCA1 protein (p.Asn113Lys). The asparagine residue is moderately conserved and there is a moderate physicochemical difference between asparagine and lysine. 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 conditions. ClinVar contains an entry for this variant (Variation ID: 89058). 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 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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