ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.6196G>A (p.Val2066Ile) (rs397507365)

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 RCV000132349 SCV000187438 uncertain significance Hereditary cancer-predisposing syndrome 2014-05-08 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (deleterious) and/or completely conserved position in appropriate species
Michigan Medical Genetics Laboratories,University of Michigan RCV000031605 SCV000267791 uncertain significance Breast-ovarian cancer, familial 2 2016-04-21 criteria provided, single submitter clinical testing
Invitae RCV000476966 SCV000549676 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-12-13 criteria provided, single submitter clinical testing This sequence change replaces valine with isoleucine at codon 2066 of the BRCA2 protein (p.Val2066Ile). The valine residue is highly conserved and there is a small physicochemical difference between valine and isoleucine. This variant is not present in population databases (ExAC no frequency). This variant has not been reported in the literature in individuals with BRCA2-related disease. ClinVar contains an entry for this variant (Variation ID: 38024). 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 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.
GeneDx RCV000588799 SCV000564789 uncertain significance not provided 2018-03-18 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.6196G>A at the cDNA level, p.Val2066Ile (V2066I) at the protein level, and results in the change of a Valine to an Isoleucine (GTT>ATT). Using alternate nomenclature, this variant would be defined as BRCA2 6424G>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Val2066Ile was not observed in large population cohorts (Lek 2016). Since Valine and Isoleucine share similar properties, this is considered a conservative amino acid substitution. BRCA2 Val2066Ile occurs at a position that is conserved across species and is located in the BRC8 domain and the RAD51 binding domain (Cole 2011, Roy 2012). 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 Val2066Ile is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000855632 SCV000694946 uncertain significance not specified 2019-04-29 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.6196G>A (p.Val2066Ile) results in a conservative amino acid change located in the BRCA2 repeat of the encoded protein sequence. Four of five in-silico tools predict a damaging effect of the variant on protein function. The variant was absent in 250212 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.6196G>A, has been reported in the literature in one individual affected with cervical squamous cell carcinoma (Muller_2015). This report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrences with other pathogenic variant(s) have been reported (BRCA2 c.7558C>T , p.Arg2520X, internal specimen), providing supporting evidence for a benign role.To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Five clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All laboratories classified the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as a VUS - possibly benign variant.
Counsyl RCV000031605 SCV000785801 uncertain significance Breast-ovarian cancer, familial 2 2017-12-05 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588799 SCV000889087 uncertain significance not provided 2017-12-05 criteria provided, single submitter clinical testing
Color RCV000132349 SCV000906132 uncertain significance Hereditary cancer-predisposing syndrome 2018-07-09 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000031605 SCV000054212 uncertain significance Breast-ovarian cancer, familial 2 2012-01-09 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.