ClinVar Miner

Submissions for variant NM_000059.3(BRCA2):c.9649-6dup (rs276174929)

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
Invitae RCV000231177 SCV000283371 likely benign Hereditary breast and ovarian cancer syndrome 2020-12-01 criteria provided, single submitter clinical testing
GeneDx RCV000478283 SCV000571057 likely benign not specified 2018-01-25 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.
Color Health, Inc RCV000776227 SCV000911432 likely benign Hereditary cancer-predisposing syndrome 2017-12-18 criteria provided, single submitter clinical testing
Women's Health and Genetics/Laboratory Corporation of America, LabCorp RCV000478283 SCV001572425 likely benign not specified 2021-04-11 criteria provided, single submitter clinical testing Variant summary: BRCA2 c.9649-6dupT alters a non-conserved nucleotide located close to a canonical splice site and therefore could affect mRNA splicing, leading to a significantly altered protein sequence. 4/4 computational tools predict no significant impact on normal splicing. However, these predictions have yet to be confirmed by functional studies. The variant allele was found at a frequency of 3.3e-05 in 242742 control chromosomes. The available data on variant occurrences in the general population are insufficient to allow any conclusion about variant significance. c.9649-6dupT has been reported in the literature as a VUS in at-least one individual affected with breast cancer (example, Bhaskaran_2019). These report(s) do not provide unequivocal conclusions about association of the variant with Hereditary Breast And Ovarian Cancer Syndrome. To our knowledge, no experimental evidence demonstrating an impact on protein function has been reported. Three 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 likely benign. Based on the peer consensus and the evidence outlined above, the variant was classified as likely benign.
Breast Cancer Information Core (BIC) (BRCA2) RCV000114147 SCV000147692 uncertain significance Breast-ovarian cancer, familial 2 2001-10-29 no assertion criteria provided clinical testing
Department of Pathology and Laboratory Medicine,Sinai Health System RCV001354910 SCV001549638 uncertain significance not provided no assertion criteria provided clinical testing The BRCA2 c.9649-6dup variant was identified in 1 of 1652 proband chromosomes (frequency: 0.0006) from individuals or families with hereditary breast and ovarian cancer and was not identified in 2068 control chromosomes from healthy individuals (Bhaskaran 2019). The variant was identified in dbSNP (rs276174929) as “with uncertain significance allele”, ClinVar (classified as likely benign by Invitae, Color and GeneDx; and as uncertain significance by BIC), LOVD 3.0 (observed 2x) and UMD-LSDB (observed 2x). The variant was identified in control databases in 8 of 242,742 chromosomes at a frequency of 0.00003 (Genome Aggregation Database Feb 27, 2017). The variant was observed in the following populations: East Asian in 1 of 18,066 chromosomes (freq: 0.00006), Finnish in 1 of 19,514 chromosomes (freq: 0.00005), European in 4 of 111,372 chromosomes (freq: 0.00004), South Asian in 1 of 29,068 chromosomes (freq: 0.00003), and Latino in 1 of 33,502 chromosomes (freq: 0.00003); it was not observed in the African, Ashkenazi Jewish or Other populations. The c.9649-6dup variant is located in the 3' splice region but does not affect the invariant -1 and -2 positions. However, positions -3 and -5 to -12 are part of the splicing consensus sequence and variants involving these positions sometimes affect splicing. This variant results in the addition of one thymine base into a polyT tract, decreasing the likelihood that this variant has clinical significance. In addition, 4 out of 4 in silico or computational prediction software programs (SpliceSiteFinder, MaxEntScan, NNSPLICE, GeneSplicer) do not predict a difference in splicing. In summary, based on the above information the clinical significance of this variant cannot be determined with certainty at this time. This variant is 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.