ClinVar Miner

Submissions for variant NM_007294.4(BRCA1):c.2215A>G (p.Lys739Glu) (rs56329598)

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Total submissions: 3
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000561453 SCV000665916 uncertain significance Hereditary cancer-predisposing syndrome 2019-09-11 criteria provided, single submitter clinical testing Insufficient evidence
Integrated Genetics/Laboratory Corporation of America RCV000587563 SCV000698930 uncertain significance not provided 2016-05-02 criteria provided, single submitter clinical testing Variant summary: The BRCA1 c.2215A>G variant affects a non-conserved nucleotide, resulting in an amino acid change from Lys to Glu. 4/4 in-silico tools predict a benign outcome for this variant (SNPs&GO not captured due to low reliability index). This variant was found in 1/121324 control chromosomes at a frequency of 0.0000082, which does not exceed maximal expected frequency of a pathogenic BRCA1 allele (0.0010005). The variant of interest has not, to our knowledge, been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. Because of the absence of clinical information and the lack of functional studies, the variant was classified as a variant of uncertain significance (VUS) until additional information becomes available.
Invitae RCV001203880 SCV001375059 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-09-04 criteria provided, single submitter clinical testing This sequence change replaces lysine with glutamic acid at codon 739 of the BRCA1 protein (p.Lys739Glu). 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 (rs56329598, ExAC 0.001%). This variant has not been reported in the literature in individuals with BRCA1-related conditions. ClinVar contains an entry for this variant (Variation ID: 481479). 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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