ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6009_6011AGA[1] (p.Glu2004del) (rs761799851)

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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 RCV000573072 SCV000673140 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
GeneDx RCV000485814 SCV000570381 uncertain significance not provided 2017-11-17 criteria provided, single submitter clinical testing This in-frame deletion of 3 nucleotides in BRCA2 is denoted c.6012_6014delAGA at the cDNA level and p.Glu2004del (E2004del) at the protein level. Using alternate nomenclature, this variant would be defined as BRCA2 6240_6242delAGA or 6240del3. The normal sequence, with the bases that are deleted in brackets, is TAGA[delAGA]TAGT. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. This deletion of a single Glutamic Acid residue occurs within the BRC7 domain and the RAD51 binding domain (Cole 2011, Roy 2012). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Since in-frame deletions may or may not inhibit proper protein functioning, the clinical significance of this finding remains unclear at this time and we consider BRCA2 Glu2004del to be a variant of uncertain significance.
Invitae RCV000467168 SCV000549490 uncertain significance Hereditary breast and ovarian cancer syndrome 2016-12-24 criteria provided, single submitter clinical testing This sequence change deletes 3 nucleotides from exon 11 of the BRCA2 mRNA (c.6012_6014delAGA). This leads to the deletion of 1 amino acid residue in the BRCA2 protein (p.Glu2004del) but otherwise preserves the integrity of the reading frame. This variant is present in population databases (rs761799851, ExAC 0.002%) but has not been reported in the literature in individuals with a BRCA2-related disease. Experimental studies and prediction algorithms are not available for this variant, and the functional significance of the deleted amino acid is currently unknown. In summary, this is a rare in-frame codon loss with unknown impact on protein function. There is no indication that this variant causes disease, but the evidence is insufficient at this time to prove that conclusively. Therefore, it has been classified as a Variant of Uncertain Significance.

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