ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.4046T>C (p.Ile1349Thr) (rs80358654)

Minimum review status: Collection method:
Minimum conflict level:
ClinVar version:
Total submissions: 9
Download table as spreadsheet
Submitter RCV SCV Clinical significance Condition Last evaluated Review status Method Comment
Evidence-based Network for the Interpretation of Germline Mutant Alleles (ENIGMA) RCV000113266 SCV000244444 benign Breast-ovarian cancer, familial 2 2015-08-10 reviewed by expert panel curation IARC class based on posterior probability from multifactorial likelihood analysis, thresholds for class as per Plon et al. 2008 (PMID: 18951446). Class 1 based on posterior probability = 0.0000088
Invitae RCV001087020 SCV000072349 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000044336 SCV000210600 likely benign not specified 2017-07-11 criteria provided, single submitter clinical testing This variant is considered likely benign or benign based on one or more of the following criteria: it is a conservative change, it occurs at a poorly conserved position in the protein, it is predicted to be benign by multiple in silico algorithms, and/or has population frequency not consistent with disease.
Ambry Genetics RCV000163004 SCV000213492 benign Hereditary cancer-predisposing syndrome 2014-11-19 criteria provided, single submitter clinical testing This alteration is classified as benign based on a combination of the following: population frequency, intact protein function, lack of segregation with disease, co-occurrence, RNA analysis, in silico models, amino acid conservation, lack of disease association in case-control studies, and/or the mechanism of disease or impacted region is inconsistent with a known cause of pathogenicity.
Counsyl RCV000113266 SCV000488340 benign Breast-ovarian cancer, familial 2 2016-03-03 criteria provided, single submitter clinical testing
Color Health, Inc RCV000163004 SCV000688844 likely benign Hereditary cancer-predisposing syndrome 2017-09-11 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000044336 SCV000694737 likely benign not specified 2019-04-18 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.4046T>C (p.Ile1349Thr) results in a non-conservative amino acid change located in the BRCA2 repeat region, between the repeats BRC2 and BRC3 (IPR002093) of the encoded protein sequence. Three of five in-silico tools predict a benign effect of the variant on protein function. The variant allele was found at a frequency of 1.3e-05 in 239668 control chromosomes (gnomAD). The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. Though the variant, c.4046T>C, has been reported in the literature in 2 individuals affected with triple-negative breast cancer (Wong-Brown 2015), this report does not provide unequivocal conclusions about association of the variant with Hereditary Breast and Ovarian Cancer. Co-occurrence with another pathogenic variant has been reported (BRCA2 c.8770G>T / p.Glu2924Ter; in the BIC database), providing supporting evidence for a benign role. In addition, multifactorial probability models, performing systematic assessments of variants of unknown significance in the BRCA genes, which included analysis of co-occurrence in trans with known deleterious mutations, personal and family history of cancer, tumor pathology and co-segregation with disease in pedigrees, predicted this variant to be neutral (Easton 2007 and Lindor 2012). To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Six submitters including and one expert panel have provided clinical-significance assessments for this variant to ClinVar after 2014 without evidence for independent evaluation. All submitters including the expert panel have classified the variant as benign (n=2) or likely benign (n=4). Based on the evidence outlined above, the variant was classified as likely benign until additional clinical and functional evidence become available.
Quest Diagnostics Nichols Institute San Juan Capistrano RCV000588400 SCV000889037 likely benign not provided 2020-07-03 criteria provided, single submitter clinical testing
Breast Cancer Information Core (BIC) (BRCA2) RCV000113266 SCV000146363 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.