ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.7006C>T (p.Arg2336Cys) (rs431825347)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 6
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000132214 SCV000187296 likely benign Hereditary cancer-predisposing syndrome 2018-03-09 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient or conflicting evidence,In silico models in agreement (benign),Other data supporting benign classification
GeneDx RCV000588307 SCV000210410 uncertain significance not provided 2018-06-27 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.7006C>T at the cDNA level, p.Arg2336Cys (R2336C) at the protein level, and results in the change of an Arginine to a Cysteine (CGC>TGC). This variant, also defined as BRCA2 7234C>T using alternate nomenclature, has been observed in at least two individuals with a personal and/or family history of breast and/or ovarian cancer (Levanat 2012, Alemar 2017). BRCA2 Arg2336Cys was not observed at a significant allele frequency in large population cohorts (Lek 2016). This variant is not located in a known functional domain. 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 Arg2336Cys is pathogenic or benign. We consider it to be a variant of uncertain significance.
Integrated Genetics/Laboratory Corporation of America RCV000588307 SCV000695020 uncertain significance not provided 2017-05-30 criteria provided, single submitter clinical testing Variant summary: The BRCA2 c.7006C>T (p.Arg2336Cys) variant involves the alteration of a non-conserved nucleotide and 3/5 in silico tools predict a benign outcome, although these predictions have yet to be functionally assessed. The variant is located outside of any functional domain or repeat. The variant affects the second nucleotide from the end of exon 13, and, although the 5/5 programs in Alamut predict that this variant does not have a major effect a splicing, no functional studies supporting this notion were published at the time of evaluation. The variant is present in the large control population dataset of gnomAD at a frequency 0.0000146 (4/273854chrs tested). This frequency does not exceed the estimated maximal expected allele frequency of a pathogenic variant in BRCA2 gene (0.00075). Multiple clinical diagnostic laboratories/reputable databases classified this variant as Uncertain significance/Likely Benign. In the literature, the variant has been reported in at least one patient with HBOC. Taken together, this variant has been classified as a "Variant of Uncertain Significance" until additional evidence becomes available.
Invitae RCV000476201 SCV000549540 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-10-03 criteria provided, single submitter clinical testing This sequence change replaces arginine with cysteine at codon 2336 of the BRCA2 protein (p.Arg2336Cys). The arginine residue is weakly conserved and there is a large physicochemical difference between arginine and cysteine. This variant is not present in population databases (rs431825347, ExAC no frequency). This variant has been reported in individuals with a personal and/or family history of breast and/or ovarian cancer (PMID: 22366370, Invitae). However, in one of these individuals a pathogenic allele were also identified in BRCA2, which suggests that this c.7006C>T variant was not the primary cause of disease. ClinVar contains an entry for this variant (Variation ID: 96845). 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 cysteine amino acid residue is also 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. Algorithms developed to predict the effect of sequence changes on RNA splicing suggest that this variant may alter RNA splicing, but this prediction has not been confirmed by published transcriptional studies. Several different missense substitutions at this codon (p.Arg2336Pro, p.Arg2336Leu, p.Arg2336His) have been determined to be pathogenic, primarily due to effects on mRNA splicing (PMID: 16792514, 22505045). However, in each of these cases the nucleotide change occurred at position c.7007 (the final nucleotide of the exon, which is part of consensus donor splice site (PMID: 17576681, 9536098)). Therefore, the importance of the arginine residue, and of the nucleotide at position c.7006, is unclear at this time. 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.
Michigan Medical Genetics Laboratories,University of Michigan RCV000082966 SCV000196000 uncertain significance Breast-ovarian cancer, familial 2 2014-11-03 criteria provided, single submitter clinical testing
Sharing Clinical Reports Project (SCRP) RCV000082966 SCV000115040 uncertain significance Breast-ovarian cancer, familial 2 2011-10-18 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.