ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.1478C>T (p.Pro493Leu) (rs786202916)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 8
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000165981 SCV000216739 likely benign Hereditary cancer-predisposing syndrome 2018-12-01 criteria provided, single submitter clinical testing In silico models in agreement (benign);Other strong data supporting benign classification
Counsyl RCV000239257 SCV000488285 uncertain significance Breast-ovarian cancer, familial 2 2016-02-16 criteria provided, single submitter clinical testing
GeneDx RCV000587856 SCV000566694 uncertain significance not provided 2018-09-20 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.1478C>T at the cDNA level, p.Pro493Leu (P493L) at the protein level, and results in the change of a Proline to a Leucine (CCA>CTA). Using alternate nomenclature, this variant would be defined as BRCA2 1706C>T. This variant was observed in at least two individuals with breast cancer (Yang 2017). BRCA2 Pro493Leu was not observed in large population cohorts (Lek 2016). This variant is not located in a known functional domain. In-silico analyses, including protein predictors and evolutionary conservation, support that this variant does not alter protein structure or function. Based on currently available evidence, it is unclear whether BRCA2 Pro493Leu is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Department of Pathology and Laboratory Medicine,Sinai Health System RCV000486205 SCV000591747 likely benign not specified 2012-11-15 criteria provided, single submitter clinical testing
Invitae RCV000534241 SCV000635162 uncertain significance Hereditary breast and ovarian cancer syndrome 2019-11-14 criteria provided, single submitter clinical testing This sequence change replaces proline with leucine at codon 493 of the BRCA2 protein (p.Pro493Leu). The proline residue is weakly conserved and there is a moderate physicochemical difference between proline and leucine. This variant is not present in population databases (ExAC no frequency). This variant has been observed in individuals with breast cancer (PMID:28664506, Invitae). However, in one of these individuals a pathogenic allele was also identified in BRCA2, which suggests that this c.1478C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 186393). 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 leucine 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 RCV000486205 SCV000694542 uncertain significance not specified 2020-08-13 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.1478C>T (p.Pro493Leu) 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 4.1e-06 in 243540 control chromosomes (gnomAD and publication data). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.1478C>T has been reported in the literature in two individuals affected with Breast Cancer (Yang_2017). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six other clinical diagnostic laboratories have submitted clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. Multiple laboratories reported the variant with conflicting assessments (4 calling it VUS, and 2 classifying it as Likely Benign). Based on the evidence outlined above, the variant was classified as uncertain significance.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000587856 SCV000888981 uncertain significance not provided 2018-12-18 criteria provided, single submitter clinical testing
Color RCV000165981 SCV000903160 likely benign Hereditary cancer-predisposing syndrome 2016-10-11 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.