ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9284A>G (p.Asp3095Gly) (rs1060502443)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 2
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
ARUP Laboratories, Molecular Genetics and Genomics, ARUP Laboratories RCV000757042 SCV000885099 uncertain significance not provided 2018-04-02 criteria provided, single submitter clinical testing The BRCA2 c.9284A>G; p.Asp3095Gly variant, to our knowledge, is not reported in the medical literature but is reported as likely pathogenic by one laboratory in ClinVar (Variation ID: 409512). It is absent from the general population databases (1000 Genomes Project, Exome Variant Server, and Genome Aggregation Database), indicating it is not a common polymorphism. The aspartic acid at codon 3095 is highly conserved and computational algorithms (PolyPhen2, SIFT) predict this variant is deleterious. Additionally, another variant at this codon (p.Asp3095Glu) has been reported as pathogenic by several laboratories in ClinVar (Variation ID: 52805) and functional analyses of this variant protein demonstrate impaired homology-directed repair activity (Guidugli 2013). Due to the lack of clinical information regarding p.Asp3095Gly, its significance cannot be determined with certainty. References: Guidugli L et al. A classification model for BRCA2 DNA binding domain missense variants based on homology-directed repair activity. Cancer Res. 2013 Jan 1;73(1):265-75.
Invitae RCV000461281 SCV000549657 likely pathogenic Hereditary breast and ovarian cancer syndrome 2018-02-08 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 3095 of the BRCA2 protein (p.Asp3095Gly). The aspartic acid residue is highly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is not present in population databases (ExAC no frequency). This variant has been shown to segregate with breast cancer in one family (Invitae). ClinVar contains an entry for this variant (Variation ID: 409512). A different missense substitution at this codon (p.Asp3095Glu) has been determined to be pathogenic (PMID: 18451181, 18951446, 22678057). This suggests that the aspartic acid residue is critical for BRCA2 protein function and that other missense substitutions at this position may also be pathogenic. 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. In summary, this variant is a rare missense change that segregates with disease in one family, and affects a residue that is presumed to be important for protein function. This evidence indicates that the variant is pathogenic, but additional data is needed to prove that conclusively. Therefore, this variant has been classified as Likely Pathogenic.

The information on this website is not intended for direct diagnostic use or medical decision-making without review by a genetics professional. Individuals should not change their health behavior solely on the basis of information contained on this website. Neither the University of Utah nor the National Institutes of Health independently verfies the submitted information. If you have questions about the information contained on this website, please see a health care professional.