ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8866G>C (p.Glu2956Gln) (rs142040996)

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Total submissions: 8
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Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220440 SCV000276568 uncertain significance Hereditary cancer-predisposing syndrome 2018-03-02 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
GeneDx RCV000589427 SCV000565943 uncertain significance not provided 2015-03-12 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8866G>C at the cDNA level, p.Glu2956Gln (E2956Q) at the protein level, and results in the change of a Glutamic Acid to a Glutamine (GAA>CAA). Using alternate nomenclature, this variant would be defined as BRCA2 9094G>C. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Glu2956Gln was not observed at significant allele frequency in the NHLBI Exome Sequencing Project. Since Glutamic Acid and Glutamine differ in some properties, this is considered a semi-conservative amino acid substitution. BRCA2 Glu2956Gln occurs at a position that is moderately conserved in mammals and is located within the DNA binding domain (Borg 2010). In silico analyses are inconsistent regarding the effect this variant may have on protein structure and function. Based on currently available information, it is unclear whether BRCA2 Glu2956Gln is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000589427 SCV000695181 uncertain significance not provided 2016-03-08 criteria provided, single submitter clinical testing Variant summary: c.8866G>C affects a conserved nucleotide, resulting in amino acid change from Glu to Gln. 3/4 in-silico tools predict this variant to be damaging (SNPs&GO not captured due to low reliability index). This variant was not found in 120628 control chromosomes. The variant of interest has not been reported in affected individuals via publications and/or reputable databases/clinical laboratories; nor evaluated for functional impact by in vivo/vitro studies. SCRP via ClinVar lists variant as VUS. Considering all, 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.
Counsyl RCV000031771 SCV000785615 uncertain significance Breast-ovarian cancer, familial 2 2017-10-17 criteria provided, single submitter clinical testing
Invitae RCV000690405 SCV000818089 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-09 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with glutamine at codon 2956 of the BRCA2 protein (p.Glu2956Gln). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and glutamine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in an individual with personal and family history of breast cancer (Invitae). However, in that individual another pathogenic allele (p.Trp1692Metfs*3) was also identified in the BRCA2 gene, which suggests that this c.8866G>C variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 38188). 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.
Color RCV000220440 SCV000906466 likely benign Hereditary cancer-predisposing syndrome 2016-04-08 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000589427 SCV001133950 uncertain significance not provided 2019-05-09 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031771 SCV000054379 uncertain significance Breast-ovarian cancer, familial 2 2009-06-18 no assertion criteria provided clinical testing

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