Submissions for variant NM_000059.4(BRCA2):c.9006A>T (p.Glu3002Asp)

dbSNP: rs80359153

Total submissions: 9

Submitter	RCV	SCV	Clinical significance	Condition	Last evaluated	Review status	Method	Comment
Invitae	RCV000045686	SCV000073699	likely benign	Hereditary breast ovarian cancer syndrome	2023-11-30	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.
Ambry Genetics	RCV000129004	SCV000172900	likely benign	Hereditary cancer-predisposing syndrome	2020-01-23	criteria provided, single submitter	clinical testing	This alteration is classified as likely benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
CSER _CC_NCGL, University of Washington	RCV000045686	SCV000212198	uncertain significance	Hereditary breast ovarian cancer syndrome	2015-03-11	criteria provided, single submitter	research
Quest Diagnostics Nichols Institute San Juan Capistrano	RCV000074558	SCV000600837	uncertain significance	not specified	2016-10-19	criteria provided, single submitter	clinical testing
Color Diagnostics, LLC DBA Color Health	RCV000129004	SCV000903962	likely benign	Hereditary cancer-predisposing syndrome	2017-09-27	criteria provided, single submitter	clinical testing
Sharing Clinical Reports Project (SCRP)	RCV000083151	SCV000115225	likely benign	Breast-ovarian cancer, familial, susceptibility to, 2	2012-07-13	no assertion criteria provided	clinical testing
Breast Cancer Information Core (BIC) (BRCA2)	RCV000083151	SCV000147511	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2002-05-29	no assertion criteria provided	clinical testing
Department of Medical and Surgical Sciences, University of Bologna	RCV000083151	SCV004228457	uncertain significance	Breast-ovarian cancer, familial, susceptibility to, 2	2023-09-01	no assertion criteria provided	clinical testing	PM2(Supporting)+PP3(Supporting)+BP5(Supporting) according to ACMG/AMP classification guidelines specified for BRCA1 & BRCA2 (Classification Criteria V1.0.0 2023-09-08 - https://cspec.genome.network/cspec/ui/svi/affiliation/50087) (PMID: 38160042)