ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9542T>G (p.Met3181Arg) (rs80359225)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 5
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Invitae RCV000045853 SCV000073866 uncertain significance Hereditary breast and ovarian cancer syndrome 2018-11-30 criteria provided, single submitter clinical testing This sequence change replaces methionine with arginine at codon 3181 of the BRCA2 protein (p.Met3181Arg). The methionine residue is weakly conserved and there is a moderate physicochemical difference between methionine and arginine. 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: 52867). Algorithms developed to predict the effect of missense changes on protein structure and function do not agree on the potential impact of this missense change (SIFT: "Tolerated"; PolyPhen-2: "Possibly Damaging"; Align-GVGD: "Class C0"). An algorithm developed specifically for the BRCA2 gene (PMID: 19043619) suggests that this missense change is likely to be tolerated. However, these predictions have not been confirmed by published functional studies. 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.
GeneDx RCV000590128 SCV000210689 uncertain significance not provided 2018-08-30 criteria provided, single submitter clinical testing This variant is denoted BRCA2 c.9542T>G at the cDNA level, p.Met3181Arg (M3181R) at the protein level, and results in the change of a Methionine to an Arginine (ATG>AGG). Using alternate nomenclature, this variant would be defined BRCA2 9770T>G. This variant has not, to our knowledge, been published in the literature as pathogenic or benign. BRCA2 Met3181Arg was not observed in large population cohorts (Lek 2016). Since Methionine and Arginine differ in polarity, charge, size or other properties, this is considered a non-conservative amino acid substitution. BRCA2 Met3181Arg is located in the DNA binding domain (Yang 2002). 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 Met3181Arg is a pathogenic or benign variant. We consider it to be a variant of uncertain significance.
Ambry Genetics RCV000219030 SCV000275128 uncertain significance Hereditary cancer-predisposing syndrome 2018-08-06 criteria provided, single submitter clinical testing Insufficient or conflicting evidence
Integrated Genetics/Laboratory Corporation of America RCV000855634 SCV000695250 uncertain significance not specified 2019-01-15 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9542T>G (p.Met3181Arg) results in a non-conservative amino acid change located in the BRCA2, OB3 domain of the encoded protein sequence. Four of five in-silico tools predict a benign effect of the variant on protein function. The variant was absent in 246166 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9542T>G has been reported in the literature in an individual affected with Ovarian Cancer (Kowalik_2018). This report does 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. Three ClinVar submissions from clinical diagnostic laboratories (evaluation after 2014) cite the variant as uncertain significance. Based on the evidence outlined above, the variant was classified as uncertain significance.
Breast Cancer Information Core (BIC) (BRCA2) RCV000114131 SCV000147665 uncertain significance Breast-ovarian cancer, familial 2 2002-05-29 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.