ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8867A>C (p.Glu2956Ala) (rs151174152)

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Total submissions: 5
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130252 SCV000185096 likely benign Hereditary cancer-predisposing syndrome 2016-07-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Other data supporting benign classification,Co-occurence with a mutation in another gene that clearly explains a proband's phenotype
Counsyl RCV000031772 SCV000487803 uncertain significance Breast-ovarian cancer, familial 2 2015-11-17 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000781140 SCV000919001 uncertain significance not specified 2018-09-24 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8867A>C (p.Glu2956Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 7.2e-06 in 276410 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. To our knowledge, no occurrence of c.8867A>C in individuals affected with Hereditary Breast and Ovarian Cancer and no experimental evidence demonstrating its impact on protein function have been reported. Two ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cites the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Invitae RCV000476614 SCV000549760 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-23 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with alanine at codon 2956 of the BRCA2 protein (p.Glu2956Ala). 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 (rs151174152, ExAC 0.002%). This variant has not been reported in the literature in individuals with a BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 38189). 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, this variant has uncertain impact on BRCA2 function. The available evidence is currently insufficient to determine its role in disease. Therefore, it has been classified as a Variant of Uncertain Significance.
Sharing Clinical Reports Project (SCRP) RCV000031772 SCV000054380 likely benign Breast-ovarian cancer, familial 2 2012-05-01 no assertion criteria provided clinical testing

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