ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5096A>G (p.Asp1699Gly) (rs80358732)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 11
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130603 SCV000185478 uncertain significance Hereditary cancer-predisposing syndrome 2017-11-07 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence
Breast Cancer Information Core (BIC) (BRCA2) RCV000113377 SCV000146534 uncertain significance Breast-ovarian cancer, familial 2 2003-12-23 no assertion criteria provided clinical testing
Color RCV000130603 SCV000911021 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing
Counsyl RCV000113377 SCV000785237 uncertain significance Breast-ovarian cancer, familial 2 2017-06-16 criteria provided, single submitter clinical testing
EGL Genetic Diagnostics,Eurofins Clinical Diagnostics RCV000587656 SCV000225156 uncertain significance not provided 2015-03-26 criteria provided, single submitter clinical testing
GeneDx RCV000587656 SCV000279807 uncertain significance not provided 2017-09-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5096A>G at the cDNA level, p.Asp1699Gly (D1699G) at the protein level, and results in the change of an Aspartic Acid to a Glycine (GAT>GGT). Using alternate nomenclature, this variant would be defined as BRCA2 5324A>G. This variant has been observed in several individuals with breast cancer, one of whom met Hereditary Breast and Ovarian Cancer criteria, as well as in an individual with glioblastoma multiforme (Rummel 2013, Lu 2015, Fernandes 2016, Palmero 2016). BRCA2 Asp1699Gly was not observed at a significant allele frequency in 1000 Genomes. Since Aspartic Acid and Glycine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Asp1699Gly occurs at a position that is not conserved and is located in the RAD51 and POLH binding domains (Roy 2012, Buisson 2014). In silico analyses are inconsistent regarding the effect this variant may have on protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Asp1699Gly is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000587656 SCV000694828 uncertain significance not provided 2016-01-14 criteria provided, single submitter clinical testing Variant summary: The c.5096A>G variant affects a conserved nucleotide, resulting in amino acid change from Asp to Gly. 2/4 in-silico tools predict this variant to be benign. 4/5 programs in Alamut predict that this variant does not affect normal splicing. ESE finder predicts that this variant does not affect any ESE site. However, these predictions are not confirmed by experimental studies. Variant of interest has been reported in one patient with triple-negative breast cancer (Rummel_2013) and one patient with glioblastoma multiforme (Lu_2015), however, without co-segregation evidence to support the pathogenicity of this variant. This variant is found in 1/118520 control chromosomes at a frequency of 0.0000084, which does not significantly exceed maximal expected frequency of a pathogenic allele (0.0007503). In addition, multiple clinical laboratories/reputable databases classified this variant as VUS. 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.
Invitae RCV000044553 SCV000072566 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-26 criteria provided, single submitter clinical testing This sequence change replaces aspartic acid with glycine at codon 1699 of the BRCA2 protein (p.Asp1699Gly). The aspartic acid residue is weakly conserved and there is a moderate physicochemical difference between aspartic acid and glycine. This variant is present in population databases (rs80358732, ExAC 0.009%). This variant has been reported in an individual affected with breast cancer (PMID: 23192404) and in an individual with personal or family history of breast and/or ovarian cancer (PMID: 27223485). ClinVar contains an entry for this variant (Variation ID: 51765). 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. 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.
Mendelics RCV000044553 SCV000838804 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000216651 SCV000600625 uncertain significance not specified 2017-05-12 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587656 SCV000887836 uncertain significance not provided 2017-05-12 criteria provided, single submitter clinical testing

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.