ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.2683G>A (p.Ala895Thr) (rs786203045)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000166179 SCV000216954 likely benign Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Invitae RCV000548524 SCV000635238 uncertain significance Hereditary breast and ovarian cancer syndrome 2020-09-23 criteria provided, single submitter clinical testing This sequence change replaces alanine with threonine at codon 895 of the BRCA2 protein (p.Ala895Thr). The alanine residue is weakly conserved and there is a small physicochemical difference between alanine and threonine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individual(s) with oropharyngeal cancer (PMID: 28678401). ClinVar contains an entry for this variant (Variation ID: 186564). 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 threonine 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may create or strengthen a splice site, but this prediction has not been confirmed by published transcriptional 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.
Counsyl RCV000239250 SCV000785506 uncertain significance Breast-ovarian cancer, familial 2 2017-08-29 criteria provided, single submitter clinical testing
Color Health, Inc RCV000166179 SCV000906046 uncertain significance Hereditary cancer-predisposing syndrome 2019-04-19 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV001175564 SCV001339191 uncertain significance not specified 2020-03-31 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.2683G>A (p.Ala895Thr) 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 was absent in 238218 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.2683G>A has been reported in the literature in one individual affected with head and neck squamous cell carcinoma as well as one individual affected with unspecified cancer (Chandrasekharappa_2017, Jiang_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. Four ClinVar submitters (evaluation after 2014) cite the variant as uncertain significance (3x) and likely benign (1x). Based on the evidence outlined above, the variant was classified as uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000239250 SCV000297514 uncertain significance Breast-ovarian cancer, familial 2 2013-03-05 no assertion criteria provided 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.