ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8902A>G (p.Thr2968Ala) (rs587782021)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000130450 SCV000185314 uncertain significance Hereditary cancer-predisposing syndrome 2016-08-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Rarity in general population databases (dbsnp, esp, 1000 genomes),Insufficient or conflicting evidence
GeneDx RCV000588120 SCV000210487 uncertain significance not provided 2018-09-11 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.8902A>G at the cDNA level, p.Thr2968Ala (T2968A) at the protein level, and results in the change of a Threonine to an Alanine (ACC>GCC). Using alternate nomenclature, this variant would be defined as BRCA2 9130A>G. This variant has been observed in at least one individual with breast cancer (Tung 2016) and in at least one individual with prostate cancer (Paulo 2018). BRCA2 Thr2968Ala was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Thr2968Ala is located in the DNA binding domain (Yang 2002). In silico analysis, which includes protein predictors and evolutionary conservation, supports that this variant does not alter protein structure/function. Based on currently available evidence, it is unclear whether BRCA2 Thr2968Ala is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Counsyl RCV000410479 SCV000487987 uncertain significance Breast-ovarian cancer, familial 2 2015-12-10 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588120 SCV000600829 uncertain significance not provided 2019-06-30 criteria provided, single submitter clinical testing
Invitae RCV000557418 SCV000635698 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-11 criteria provided, single submitter clinical testing This sequence change replaces threonine with alanine at codon 2968 of the BRCA2 protein (p.Thr2968Ala). The threonine residue is moderately conserved and there is a small physicochemical difference between threonine and alanine. This variant is present in population databases (rs587782021, ExAC 0.009%). This variant has been reported in an individual affected with breast cancer (PMID: 26976419). ClinVar contains an entry for this variant (Variation ID: 141798). Algorithms developed to predict the effect of missense changes on protein structure and function output the following: SIFT: "Tolerated"; PolyPhen-2: "Benign"; Align-GVGD: "Class C0". The alanine amino acid residue is found in multiple mammalian species, suggesting that this missense change does not adversely affect protein function. 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.
Integrated Genetics/Laboratory Corporation of America RCV000160160 SCV000695189 uncertain significance not specified 2019-05-14 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8902A>G (p.Thr2968Ala) results in a non-conservative amino acid change in the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 8e-06 in 249760 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. The variant, c.8902A>G, has been reported in the literature in individuals affected with breast cancer or prostate cancer (Tung_2016, Paulo_2018). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance until additional information becomes available.
Mendelics RCV000557418 SCV000838888 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-07-02 criteria provided, single submitter clinical testing
Color RCV000130450 SCV000903030 uncertain significance Hereditary cancer-predisposing syndrome 2018-11-01 criteria provided, single submitter clinical testing
Mendelics RCV000410479 SCV001139237 uncertain significance Breast-ovarian cancer, familial 2 2019-05-28 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.