ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.3562A>G (p.Ile1188Val) (rs202230438)

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 RCV000132042 SCV000187102 likely benign Hereditary cancer-predisposing syndrome 2017-10-11 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: In silico models in agreement (benign),Other strong data supporting benign classification
Biesecker Lab/Human Development Section,National Institutes of Health RCV000034438 SCV000043206 variant of unknown significance not provided 2012-07-13 no assertion criteria provided research Converted during submission to Uncertain significance.
Color RCV000132042 SCV000903241 uncertain significance Hereditary cancer-predisposing syndrome 2018-10-24 criteria provided, single submitter clinical testing
GeneDx RCV000034438 SCV000210529 uncertain significance not provided 2018-06-14 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.3562A>G at the cDNA level, p.Ile1188Val (I1188V) at the protein level, and results in the change of an Isoleucine to a Valine (ATT>GTT). Using alternate nomenclature, this variant would be defined as 3790A>G. This variant has been observed in at least three individuals with breast cancer, as well as in 1/572 individuals with atherosclerosis, with no specific information about cancer history (Kr?lewska 2004, Johnston 2012, Goidescu 2018). BRCA2 Ile1188Val was not observed at a significant allele frequency in large population cohorts (Lek 2016). BRCA2 Ile1188Val is located in the RAD51 binding domain (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 Ile1188Val is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
GeneKor MSA RCV000132042 SCV000821935 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-01 criteria provided, single submitter clinical testing
Integrated Genetics/Laboratory Corporation of America RCV000779929 SCV000916868 uncertain significance not specified 2017-09-25 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.3562A>G (p.Ile1188Val) variant involves the alteration of a non-conserved nucleotide. 4/4 in silico tools predict a benign outcome for this variant (SNPsandGO not captured due to low reliability index). This variant was found in 2/276844 control chromosomes at a frequency of 0.0000072, which does not exceed the estimated maximal expected allele frequency of a pathogenic BRCA2 variant (0.0007503). The variant has not, to our knowledge, been reported in affected individuals in the literature. In addition, multiple clinical diagnostic laboratories/reputable databases classified this variant as uncertain significance. Taken together, this variant is classified as VUS.
Invitae RCV000465606 SCV000549504 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-09-27 criteria provided, single submitter clinical testing This sequence change replaces isoleucine with valine at codon 1188 of the BRCA2 protein (p.Ile1188Val). The isoleucine residue is weakly conserved and there is a small physicochemical difference between isoleucine and valine. This variant is present in population databases (rs202230438, ExAC 0.001%). This variant has been observed in several individuals affected with breast cancer (PMID: 29785153). ClinVar contains an entry for this variant (Variation ID: 41547). 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 valine 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.

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.