ClinVar Miner

Submissions for variant NM_005591.3(MRE11):c.1139G>A (p.Arg380His) (rs587781646)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 3
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Ambry Genetics RCV000129776 SCV000184585 uncertain significance Hereditary cancer-predisposing syndrome 2017-09-25 criteria provided, single submitter clinical testing Lines of evidence used in support of classification: Insufficient evidence
Invitae RCV000524511 SCV000547431 uncertain significance Ataxia-telangiectasia-like disorder 2018-09-27 criteria provided, single submitter clinical testing This sequence change replaces arginine with histidine at codon 380 of the MRE11 protein (p.Arg380His). The arginine residue is highly conserved and there is a small physicochemical difference between arginine and histidine. This variant is present in population databases (rs587781646, ExAC 0.009%). This variant has been observed in individuals with prostate cancer or breast cancer (PMID: 24556621, 29371908) and in one family with breast and ovarian cancer (PMID: 26534844). ClinVar contains an entry for this variant (Variation ID: 141307). 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.
Integrated Genetics/Laboratory Corporation of America RCV000780433 SCV000917679 uncertain significance not specified 2018-11-20 criteria provided, single submitter clinical testing Variant summary: MRE11A c.1139G>A (p.Arg380His) results in a non-conservative amino acid change located in the Mre11, DNA-binding domain of the encoded protein sequence. Five of five in-silico tools predict a damaging effect of the variant on protein function. The variant allele was found at a frequency of 3.2e-05 in 277040 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.1139G>A has been reported in the literature in individuals affected with Hereditary Breast and Ovarian Cancer (Dominguez-Valentin_2018, Li_2015, Leongamornlert_2014). These reports do not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Two 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 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.