ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.5711T>A (p.Leu1904His) (rs876658494)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 7
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000220859 SCV000273803 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-05 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign)
GeneDx RCV000657071 SCV000279512 uncertain significance not provided 2017-11-29 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.5711T>A at the cDNA level, p.Leu1904His (L1904H) at the protein level, and results in the change of a Leucine to a Histidine (CTT>CAT). Using alternate nomenclature, this variant would be defined as BRCA2 5939T>A. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Leu1904His was not observed in large population cohorts (Lek 2016). Since Leucine and Histidine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Leu1904His is located in the RAD51 binding domain (Roy 2012). In-silico analyses, including protein predictors and evolutionary conservation, support a deleterious effect. Based on currently available evidence, it is unclear whether BRCA2 Leu1904His is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Invitae RCV000232933 SCV000283270 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-26 criteria provided, single submitter clinical testing This sequence change replaces leucine with histidine at codon 1904 of the BRCA2 protein (p.Leu1904His). The leucine residue is weakly conserved and there is a moderate physicochemical difference between leucine and histidine. 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: 230305). 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 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.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000214753 SCV000591991 uncertain significance not specified 2014-04-17 criteria provided, single submitter clinical testing
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000214753 SCV000600660 uncertain significance not specified 2017-03-10 criteria provided, single submitter clinical testing
Counsyl RCV000663230 SCV000786432 uncertain significance Breast-ovarian cancer, familial 2 2018-05-02 criteria provided, single submitter clinical testing
Color RCV000220859 SCV000904848 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-16 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.