ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3329A>C (p.Glu1110Ala) (rs587782072)

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Total submissions: 4
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000570799 SCV000668537 uncertain significance Hereditary cancer-predisposing syndrome 2018-02-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Color RCV000570799 SCV000688798 uncertain significance Hereditary cancer-predisposing syndrome 2018-05-08 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000587928 SCV000694691 uncertain significance not provided 2016-04-22 criteria provided, single submitter clinical testing Variant summary: The variant of interest affects a conserved nucleotide and results in a replacement of a medium size and acidic Glutamic acid (E) with a small size and hydrophobic Alanine (A). 5/5 in silico tools predict disease causing outcome for this substitution. The variant was observed in the large and broad cohorts of the ExAC project at an allele frequency of 1/118496 which does not exceed the maximal expected allele frequency of a disease causing BRCA2 allele (1/13000). To our knowledge, the variant function was not reported in patients and studies assessing the impact the variant may have on BRCA2 function were not published at the time of scoring either. Due to lack of clinical data and functional studies the variant was classified as a variant of uncertain significance until more information becomes available.
Invitae RCV000204123 SCV000259690 uncertain significance Hereditary breast and ovarian cancer syndrome 2017-12-06 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 1110 of the BRCA2 protein (p.Glu1110Ala). The glutamic acid residue is highly conserved and there is a moderate physicochemical difference between glutamic acid and alanine. This variant is present in population databases (rs587782072, ExAC 0.01%). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 219682). 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 disruptive, 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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