ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9006A>T (p.Glu3002Asp) (rs80359153)

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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 RCV000129004 SCV000172900 uncertain significance Hereditary cancer-predisposing syndrome 2016-09-22 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (deleterious) and/or completely conserved position in appropriate species,Other data supporting benign classification,Well-characterized mutation at same position,Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000083151 SCV000147511 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
CSER_CC_NCGL; University of Washington Medical Center RCV000045686 SCV000212198 uncertain significance Hereditary breast and ovarian cancer syndrome 2015-03-11 criteria provided, single submitter research
Color RCV000129004 SCV000903962 likely benign Hereditary cancer-predisposing syndrome 2017-09-27 criteria provided, single submitter clinical testing
GeneDx RCV000656809 SCV000108643 uncertain significance not provided 2017-10-16 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9006A>T at the cDNA level, p.Glu3002Asp (E3002D) at the protein level, and results in the change of a Glutamic Acid to an Aspartic Acid (GAA>GAT). Using alternate nomenclature, this variant would be defined as BRCA2 9234A>T. This variant has been reported to disrupt an exonic splicing enhancer (ESE) and to strengthen a cryptic acceptor site that is 51 nucleotides downstream of the canonical acceptor site, resulting in the production of both the canonical transcript (69%) as well as aberrant transcripts (31%) (Acedo 2012). Fackenthal et al. (2016) demonstrated that use of this cryptic acceptor site may be a naturally occurring transcript, observed at minor frequencies. BRCA2 Glu3002Asp was shown to have mild to moderate effects on BRCA2 and Filamin A interaction, cellular multinucleation, unresolved cytoplasmic bridges, and homology-directed DNA break repair (HDR) activity; a multifactorial likelihood model calculated its probability of neutrality as 0.94 (Mondal 2012, Guidugli 2013). BRCA2 Glu3002Asp was not observed in large population cohorts (Lek 2016). Since Glutamic Acid and Aspartic Acid share similar properties, this is considered a conservative amino acid substitution. BRCA2 Glu3002Asp occurs at a position that is conserved across species and is located in the DNA binding domain (Borg 2010). In silico analyses predict that this variant is probably damaging to protein structure and function. Based on currently available information and internal data, it is unclear whether BRCA2 Glu3002Asp is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000045686 SCV000073699 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-06-27 criteria provided, single submitter clinical testing This sequence change replaces glutamic acid with aspartic acid at codon 3002 of the BRCA2 protein (p.Glu3002Asp). The glutamic acid residue is highly conserved and there is a small physicochemical difference between glutamic acid and aspartic acid. This variant is not present in population databases (rs80359153, ExAC no frequency). This variant has been reported in individuals in the Breast Cancer Information Core (BIC) database (PMID: 10923033). However, in individuals reported in the database, a pathogenic allele was also identified in BRCA1, which suggests that this c.9006A>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 52725) Experimental studies have suggested that this variant may weakly affect mRNA splicing of the BRCA2 transcript (PMID: 22632462). Additional studies have shown intermediate function of this variant in homology-directed DNA break repair assays (PMID: 23108138, 22771033, 24323938). The clinical significance of these findings 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.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000074558 SCV000600837 uncertain significance not specified 2016-10-19 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000083151 SCV000115225 likely benign Breast-ovarian cancer, familial 2 2012-07-13 no assertion criteria provided clinical testing

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