ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.8687G>A (p.Arg2896His) (rs80359128)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 13
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV001086184 SCV000073615 likely benign Hereditary breast and ovarian cancer syndrome 2020-11-06 criteria provided, single submitter clinical testing
Ambry Genetics RCV000129089 SCV000183797 likely benign Hereditary cancer-predisposing syndrome 2018-12-31 criteria provided, single submitter clinical testing in silico models in agreement (benign);Other data supporting benign classification
Counsyl RCV000077448 SCV000488098 uncertain significance Breast-ovarian cancer, familial 2 2015-12-29 criteria provided, single submitter clinical testing
GeneDx RCV000034466 SCV000516569 likely benign not provided 2021-04-07 criteria provided, single submitter clinical testing This variant is associated with the following publications: (PMID: 22703879, 19043619, 24817641, 22476429, 25348012, 31131967)
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000418186 SCV000695173 uncertain significance not specified 2020-12-28 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.8687G>A (p.Arg2896His) results in a non-conservative amino acid change located in the tower domain within the OB2 fold (Karchin_2008) in the DNA binding region of 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 2e-05 in 252456 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.8687G>A has been reported in the literature in individuals affected with a personal and/or family history of breast and/or ovarian cancer (e.g. Lu_2012, Farra_2019), but was found also in healthy controls (e.g. Johnston_2012, and in the FLOSSIES database). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. At least one publication reported experimental evidence evaluating an impact on protein function, and demonstrated that the variant protein had a similar activity to the wild type in a homology-directed repair assay (Karchin_2008). Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation, and classified the variant as VUS (1x), likely benign (4x) or benign (1x). Based on the evidence outlined above, the variant was classified as VUS-possibly benign.
Color Health, Inc RCV000129089 SCV000902894 benign Hereditary cancer-predisposing syndrome 2016-11-21 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000034466 SCV001133944 likely benign not provided 2019-05-10 criteria provided, single submitter clinical testing
CeGaT Praxis fuer Humangenetik Tuebingen RCV000034466 SCV001746179 uncertain significance not provided 2021-04-01 criteria provided, single submitter clinical testing
Research and Development, ARUP Laboratories RCV001642550 SCV001852809 uncertain significance Breast-ovarian cancer, familial 2; Breast-ovarian cancer, familial 1; Hereditary breast and ovarian cancer syndrome 2020-01-20 criteria provided, single submitter curation
Biesecker Lab/Clinical Genomics Section,National Institutes of Health RCV000034466 SCV000043232 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Sharing Clinical Reports Project (SCRP) RCV000077448 SCV000109246 benign Breast-ovarian cancer, familial 2 2010-12-08 no assertion criteria provided clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000077448 SCV000147439 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001353522 SCV000592222 likely benign Malignant tumor of breast no assertion criteria provided clinical testing The p.Arg2896His variant is listed 3 times in the BIC database. It is listed in dbSNP database as coming from a "clinical source" (ID#: rs80359128) but no frequency information was provided, and so the frequency in the general population is not known. The p.Arg289 residue is not highly conserved in mammals and the variant amino acid histidine (His) is present in rat, mouse and chicken, increasing the likelihood this variant does not have important functional or clinical signficance. In addition, computational analyses (SIFT, PolyPhen2, and AlignGVGD) do not suggest a high likelihood of impact to the protein, but this information is not predictive enough to rule out pathogenicity. In addition, one in-silico study reported this variant as neutral (Karchin 2008). In summary, based on the current information presented above, this variant is predicted benign.

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.